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Does Buserelin and Disopyramide interact?

•Drug A: Buserelin •Drug B: Disopyramide •Severity: MODERATE •Description: The therapeutic efficacy of Disopyramide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, ventricular pre-excitation and cardiac dysrhythmias. It is a Class Ia antiarrhythmic drug. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Disopyramide is an anti-arrhythmic drug indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia that are life-threatening. At therapeutic plasma levels, disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Disopyramide is a Type 1A antiarrhythmic drug (ie, similar to procainamide and quinidine). It inhibits the fast sodium channels. In animal studies Disopyramide decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Nearly complete •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 50%-65% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite and 10% as the other metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 6.7 hours (range 4-10 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =580 mg/kg in rats •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Norpace, Rythmodan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Disopyramide is a class 1A antiarrhythmic agent used to treat life-threatening ventricular arrhythmias.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Disopyramide interact? Information: •Drug A: Buserelin •Drug B: Disopyramide •Severity: MODERATE •Description: The therapeutic efficacy of Disopyramide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, ventricular pre-excitation and cardiac dysrhythmias. It is a Class Ia antiarrhythmic drug. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Disopyramide is an anti-arrhythmic drug indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia that are life-threatening. At therapeutic plasma levels, disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Disopyramide is a Type 1A antiarrhythmic drug (ie, similar to procainamide and quinidine). It inhibits the fast sodium channels. In animal studies Disopyramide decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Nearly complete •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 50%-65% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite and 10% as the other metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 6.7 hours (range 4-10 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =580 mg/kg in rats •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Norpace, Rythmodan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Disopyramide is a class 1A antiarrhythmic agent used to treat life-threatening ventricular arrhythmias. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Disulfiram interact?

•Drug A: Buserelin •Drug B: Disulfiram •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Disulfiram is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment and management of chronic alcoholism •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body. Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake causing an accumulation of acetaldehyde in the blood producing highly unpleasant symptoms. Disulfiram blocks the oxidation of alcohol through its irreversible inactivation of aldehyde dehydrogenase, which acts in the second step of ethanol utilization. In addition, disulfiram competitively binds and inhibits the peripheral benzodiazepine receptor, which may indicate some value in the treatment of the symptoms of alcohol withdrawal, however this activity has not been extensively studied. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Disulfiram is absorbed slowly from the gastrointestinal tract (80 to 90% of oral dose). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =8.6g/kg (orally in rats). Symptoms of overdose include irritation, slight drowsiness, unpleasant taste, mild GI disturbances, and orthostatic hypotension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Antabuse •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Disulfiram Tetraethylthioperoxydicarbonic diamide Tetraethylthiuram disulfide Tetraethylthiuram disulphide •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Disulfiram is a carbamate derivative used to treat alcohol addiction.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Disulfiram interact? Information: •Drug A: Buserelin •Drug B: Disulfiram •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Disulfiram is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment and management of chronic alcoholism •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body. Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake causing an accumulation of acetaldehyde in the blood producing highly unpleasant symptoms. Disulfiram blocks the oxidation of alcohol through its irreversible inactivation of aldehyde dehydrogenase, which acts in the second step of ethanol utilization. In addition, disulfiram competitively binds and inhibits the peripheral benzodiazepine receptor, which may indicate some value in the treatment of the symptoms of alcohol withdrawal, however this activity has not been extensively studied. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Disulfiram is absorbed slowly from the gastrointestinal tract (80 to 90% of oral dose). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =8.6g/kg (orally in rats). Symptoms of overdose include irritation, slight drowsiness, unpleasant taste, mild GI disturbances, and orthostatic hypotension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Antabuse •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Disulfiram Tetraethylthioperoxydicarbonic diamide Tetraethylthiuram disulfide Tetraethylthiuram disulphide •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Disulfiram is a carbamate derivative used to treat alcohol addiction. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dofetilide interact?

•Drug A: Buserelin •Drug B: Dofetilide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dofetilide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): >90% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 3 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 60% -70% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tikosyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dofetilida Dofetilide Dofetilidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dofetilide is a class III antiarrhythmic drug used for the maintenance of normal sinus rhythm and cardioversion in cases of atrial fibrillation and atrial flutter.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Dofetilide interact? Information: •Drug A: Buserelin •Drug B: Dofetilide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dofetilide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): >90% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 3 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 60% -70% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tikosyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dofetilida Dofetilide Dofetilidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dofetilide is a class III antiarrhythmic drug used for the maintenance of normal sinus rhythm and cardioversion in cases of atrial fibrillation and atrial flutter. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Dolasetron interact?

•Drug A: Buserelin •Drug B: Dolasetron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dolasetron. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including initial and repeat courses of chemotherapy. Also used for the prevention of postoperative nausea and vomiting. This drug can be used intravenously for the treatment of postoperative nausea and vomiting. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dolasetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. It is structurally and pharmacologically related to other 5-HT 3 receptor agonists. The serontonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dolasetron is a selective serotonin 5-HT 3 receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug's pharmacological activity. The antiemetic activity of the drug is brought about through the inhibition of 5-HT 3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT 3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Orally-administered dolasetron is well absorbed •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 5.8 L/kg [adults] •Protein binding (Drug A): 15% •Protein binding (Drug B): 69-77% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Hydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation, and hydroxylation. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent cl=9.4 mL/min/kg [Healthy volunteers with IV treatment dose up to 5 mg/kg] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anzemet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dolasetron is an antinauseant and antiemetic used in chemotherapy and postoperatively.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dolasetron interact? Information: •Drug A: Buserelin •Drug B: Dolasetron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dolasetron. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including initial and repeat courses of chemotherapy. Also used for the prevention of postoperative nausea and vomiting. This drug can be used intravenously for the treatment of postoperative nausea and vomiting. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dolasetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. It is structurally and pharmacologically related to other 5-HT 3 receptor agonists. The serontonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dolasetron is a selective serotonin 5-HT 3 receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug's pharmacological activity. The antiemetic activity of the drug is brought about through the inhibition of 5-HT 3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT 3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Orally-administered dolasetron is well absorbed •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 5.8 L/kg [adults] •Protein binding (Drug A): 15% •Protein binding (Drug B): 69-77% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Hydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation, and hydroxylation. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent cl=9.4 mL/min/kg [Healthy volunteers with IV treatment dose up to 5 mg/kg] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anzemet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dolasetron is an antinauseant and antiemetic used in chemotherapy and postoperatively. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Domperidone interact?

•Drug A: Buserelin •Drug B: Domperidone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Domperidone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For management of dyspepsia, heartburn, epigastric pain, nausea, and vomiting. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Domperidone is a specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic mechanisms. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Domperidone acts as a gastrointestinal emptying (delayed) adjunct and peristaltic stimulant. The gastroprokinetic properties of domperidone are related to its peripheral dopamine receptor blocking properties. Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. Antiemetic: The antiemetic properties of domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which - among others - regulates nausea and vomiting •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 91%-93% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Side effects include galactorrhea, gynecomastia, or menstrual irregularities. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Domperidona Domperidone Domperidonum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Domperidone is a dopamine receptor antagonist used as a peristaltic stimulant and anti-emetic agent for dyspepsia, indigestion, epigastric pain, nausea, and vomiting.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Domperidone interact? Information: •Drug A: Buserelin •Drug B: Domperidone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Domperidone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For management of dyspepsia, heartburn, epigastric pain, nausea, and vomiting. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Domperidone is a specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic mechanisms. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Domperidone acts as a gastrointestinal emptying (delayed) adjunct and peristaltic stimulant. The gastroprokinetic properties of domperidone are related to its peripheral dopamine receptor blocking properties. Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. Antiemetic: The antiemetic properties of domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which - among others - regulates nausea and vomiting •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 91%-93% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Side effects include galactorrhea, gynecomastia, or menstrual irregularities. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Domperidona Domperidone Domperidonum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Domperidone is a dopamine receptor antagonist used as a peristaltic stimulant and anti-emetic agent for dyspepsia, indigestion, epigastric pain, nausea, and vomiting. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Dosulepin interact?

•Drug A: Buserelin •Drug B: Dosulepin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dosulepin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dosulepin is a tricyclic antidepressant that interacts with various receptors and transporters. It is a monoamine reuptake inhibitor with approximately equal potency for noradrenaline and 5-HT that increases the availability of these neurotransmitters at the central synapses. The metabolites of dosulepin are shown to inhibit 5HT uptake by the human blood platelet. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug. Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation. Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect. Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 84% of unchanged drug is bound to serum protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40%. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half life is approximately 20.4 hours following oral administration of 25mg dosulepin. •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral clearance is approximately 1.36 L/kg * hr following a single oral dose of 75mg dosulepin. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment. Oral lowest published toxic dose (Toxic Dose Low, TDLo) is 90 mg/kg in infants and 4.5 mg/kg in female adults. Intravenous LD50 in mouse is 31 mg/kg. Most common adverse effects involve the central nervous system (drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns), anticholinergic effects (dry mouth, sweating, urinary retention), cardiovascular system (hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects), endocrine system (altered libido), gastrointestinal system (nausea, vomiting, constipation) and blurred vision. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dosulepin Dosulepina Dosulépine Dosulepinum Dothiepin trans-dothiepin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dosulepin is a tricyclic antidepressant commonly used only in patients for whom alternative therapies are ineffective due to its toxicity potential.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dosulepin interact? Information: •Drug A: Buserelin •Drug B: Dosulepin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dosulepin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dosulepin is a tricyclic antidepressant that interacts with various receptors and transporters. It is a monoamine reuptake inhibitor with approximately equal potency for noradrenaline and 5-HT that increases the availability of these neurotransmitters at the central synapses. The metabolites of dosulepin are shown to inhibit 5HT uptake by the human blood platelet. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug. Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation. Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect. Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 84% of unchanged drug is bound to serum protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40%. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half life is approximately 20.4 hours following oral administration of 25mg dosulepin. •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral clearance is approximately 1.36 L/kg * hr following a single oral dose of 75mg dosulepin. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment. Oral lowest published toxic dose (Toxic Dose Low, TDLo) is 90 mg/kg in infants and 4.5 mg/kg in female adults. Intravenous LD50 in mouse is 31 mg/kg. Most common adverse effects involve the central nervous system (drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns), anticholinergic effects (dry mouth, sweating, urinary retention), cardiovascular system (hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects), endocrine system (altered libido), gastrointestinal system (nausea, vomiting, constipation) and blurred vision. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dosulepin Dosulepina Dosulépine Dosulepinum Dothiepin trans-dothiepin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dosulepin is a tricyclic antidepressant commonly used only in patients for whom alternative therapies are ineffective due to its toxicity potential. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Doxepin interact?

•Drug A: Buserelin •Drug B: Doxepin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Doxepin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Oral doxepin is approved for the following indications: Treatment of depression and/or anxiety. Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders. Treatment of psychotic depressive disorders with associated anxiety. Treatment of involutional depression. Treatment of manic-depressive disorder. Treatment of insomnia characterized by difficulties with sleep maintenance. Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus. Off-label, doxepin is used topically for the management of neuropathic pain. Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment. Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder. Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic. Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner. Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions. Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors. It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Equilibrium dialysis indicates a mean protein binding of 75.5% for doxepin and 76% for desmethyldoxepin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life is reported to be of 15 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed. On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Prudoxin, Silenor, Sinequan, Zonalon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Doxepin is a psychotropic agent used for the treatment of depression, anxiety, manic-depressive disorder, and insomnia.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Doxepin interact? Information: •Drug A: Buserelin •Drug B: Doxepin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Doxepin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Oral doxepin is approved for the following indications: Treatment of depression and/or anxiety. Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders. Treatment of psychotic depressive disorders with associated anxiety. Treatment of involutional depression. Treatment of manic-depressive disorder. Treatment of insomnia characterized by difficulties with sleep maintenance. Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus. Off-label, doxepin is used topically for the management of neuropathic pain. Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment. Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder. Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic. Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner. Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions. Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors. It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Equilibrium dialysis indicates a mean protein binding of 75.5% for doxepin and 76% for desmethyldoxepin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life is reported to be of 15 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed. On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Prudoxin, Silenor, Sinequan, Zonalon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Doxepin is a psychotropic agent used for the treatment of depression, anxiety, manic-depressive disorder, and insomnia. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Doxylamine interact?

•Drug A: Buserelin •Drug B: Doxylamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Doxylamine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used alone as a short-term sleep aid, in combination with other drugs as a night-time cold and allergy relief drug. Also used in combination with Vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Doxylamine is an antihistamine commonly used as a sleep aid. This drug is also used to relieve symptoms of hay fever (allergic rhinitis), hives (rash or itching), and other allergic reactions. Doxylamine is a member of the ethanolamine class of antihistamines and has anti-allergy power far superior to virtually every other antihistamine on the market, with the exception of diphenhydramine (Benadryl). It is also the most powerful over-the-counter sedative available in the United States, and more sedating than many prescription hypnotics. In a study, it was found to be superior to even the barbiturate, phenobarbital for use as a sedative. Doxylamine is also a potent anticholinergic. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Like other antihistamines, doxylamine acts by competitively inhibiting histamine at H1 receptors. It also has substantial sedative and anticholinergic effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed via the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Signs of overdose include wheezing, tightness in the chest, fever, itching, bad cough, blue skin color, fits, swelling of face, lips, tongue, or throat. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bonjesta, Dalmacol, Dayquil Sinex, Diclectin, Diclegis, Mersyndol, Nyquil Cough, Poly Hist Forte Reformulated Nov 2013, Robafen DM, Robitussin Nighttime Cough DM, Safetussin PM, Unisom, Wal-som (doxylamine) •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dossilamina Doxilamina Doxilminio Doxylamine Doxylaminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Doxylamine is an antihistamine used to treat insomnia and allergy symptoms and is used with pyridoxine in the treatment of nausea and vomiting in pregnancy.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Doxylamine interact? Information: •Drug A: Buserelin •Drug B: Doxylamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Doxylamine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used alone as a short-term sleep aid, in combination with other drugs as a night-time cold and allergy relief drug. Also used in combination with Vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Doxylamine is an antihistamine commonly used as a sleep aid. This drug is also used to relieve symptoms of hay fever (allergic rhinitis), hives (rash or itching), and other allergic reactions. Doxylamine is a member of the ethanolamine class of antihistamines and has anti-allergy power far superior to virtually every other antihistamine on the market, with the exception of diphenhydramine (Benadryl). It is also the most powerful over-the-counter sedative available in the United States, and more sedating than many prescription hypnotics. In a study, it was found to be superior to even the barbiturate, phenobarbital for use as a sedative. Doxylamine is also a potent anticholinergic. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Like other antihistamines, doxylamine acts by competitively inhibiting histamine at H1 receptors. It also has substantial sedative and anticholinergic effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed via the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Signs of overdose include wheezing, tightness in the chest, fever, itching, bad cough, blue skin color, fits, swelling of face, lips, tongue, or throat. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bonjesta, Dalmacol, Dayquil Sinex, Diclectin, Diclegis, Mersyndol, Nyquil Cough, Poly Hist Forte Reformulated Nov 2013, Robafen DM, Robitussin Nighttime Cough DM, Safetussin PM, Unisom, Wal-som (doxylamine) •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dossilamina Doxilamina Doxilminio Doxylamine Doxylaminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Doxylamine is an antihistamine used to treat insomnia and allergy symptoms and is used with pyridoxine in the treatment of nausea and vomiting in pregnancy. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dronedarone interact?

•Drug A: Buserelin •Drug B: Dronedarone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dronedarone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dronedarone is indicated for the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol. Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure. In animal studies, the use of dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis. Compared to its related compound amiodarone, dronedarone has a faster onset and offset of actions with a shorter elimination half-life and low tissue accumulation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke. Dronedarone achieves heart rate and rhythm control in atrial fibrillation. In vitro, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarone is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarone inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarone ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dronedarone is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of dronedarone and its main circulating N-debutyl metabolite are reached within 3 to 6 hours after administration with food. Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to that of the parent compound. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration. •Protein binding (Drug A): 15% •Protein binding (Drug B): The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%, respectively. Both mainly bind to albumin and are not capable of saturation. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dronedarone predominantly undergoes CYP3A-mediated hepatic metabolism. Initial metabolism of dronedarone involves N-debutylation to form the N-debutyl-dronedarone, which retains 1/10 to 1/3 of pharmacological activity of the parent compound. N-debutyl-dronedarone can be further metabolized to phenol-dronedarone via O-dealkylation and propanoic acid-dronedarone via oxidative deamination. Dronedarone can also be metabolized by CYP2D6 to form benzofuran-hydroxyl-dronedarone. Other detectable metabolites include C-dealkyl-dronedarone and dibutylamine-hydroxyl-dronedarone, along with other minor downstream metabolites with undetermined chemical structures. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration, about 84% of the labeled dose is excreted in feces and 6% is excreted in urine, mainly as metabolites. Unchanged parent compound and the N-debutyl metabolite accounted for less than 15% of the total radioactivity in the plasma. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half life ranges from 13 to 19 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the clearance ranged from 130 to 150 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In an acute toxicity study, the oral LD 50 in rat was >2,000 mg/kg. In oral studies, dronedarone showed a limited potential for toxicity in humans in acute overdose situations. However, it is recommended that the patient's cardiac rhythm and blood pressure is monitored in the event of overdose. Symptomatic and supportive treatments should be initiated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Multaq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dronedarona Dronedarone •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dronedarone is an antiarrhythmic agent used in the reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Dronedarone interact? Information: •Drug A: Buserelin •Drug B: Dronedarone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dronedarone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dronedarone is indicated for the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol. Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure. In animal studies, the use of dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis. Compared to its related compound amiodarone, dronedarone has a faster onset and offset of actions with a shorter elimination half-life and low tissue accumulation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke. Dronedarone achieves heart rate and rhythm control in atrial fibrillation. In vitro, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarone is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarone inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarone ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dronedarone is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of dronedarone and its main circulating N-debutyl metabolite are reached within 3 to 6 hours after administration with food. Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to that of the parent compound. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration. •Protein binding (Drug A): 15% •Protein binding (Drug B): The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%, respectively. Both mainly bind to albumin and are not capable of saturation. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dronedarone predominantly undergoes CYP3A-mediated hepatic metabolism. Initial metabolism of dronedarone involves N-debutylation to form the N-debutyl-dronedarone, which retains 1/10 to 1/3 of pharmacological activity of the parent compound. N-debutyl-dronedarone can be further metabolized to phenol-dronedarone via O-dealkylation and propanoic acid-dronedarone via oxidative deamination. Dronedarone can also be metabolized by CYP2D6 to form benzofuran-hydroxyl-dronedarone. Other detectable metabolites include C-dealkyl-dronedarone and dibutylamine-hydroxyl-dronedarone, along with other minor downstream metabolites with undetermined chemical structures. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration, about 84% of the labeled dose is excreted in feces and 6% is excreted in urine, mainly as metabolites. Unchanged parent compound and the N-debutyl metabolite accounted for less than 15% of the total radioactivity in the plasma. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half life ranges from 13 to 19 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the clearance ranged from 130 to 150 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In an acute toxicity study, the oral LD 50 in rat was >2,000 mg/kg. In oral studies, dronedarone showed a limited potential for toxicity in humans in acute overdose situations. However, it is recommended that the patient's cardiac rhythm and blood pressure is monitored in the event of overdose. Symptomatic and supportive treatments should be initiated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Multaq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dronedarona Dronedarone •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dronedarone is an antiarrhythmic agent used in the reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Droperidol interact?

•Drug A: Buserelin •Drug B: Droperidol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Droperidol. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Droperidol is used to produce tranquilization and to reduce the incidence of nausea and vomiting in surgical and diagnostic procedures. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Droperidol produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness. Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period. Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias, but it does not prevent other cardiac arrhythmias. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanism of action is unknown, however, droperidol causes a CNS depression at subcortical levels of the brain, midbrain, and brainstem reticular formation. It may antagonize the actions of glutamic acid within the extrapyramidal system. It may also inhibit cathecolamine receptors and the reuptake of neurotransmiters and has strong central antidopaminergic action and weak central anticholinergic action. It can also produce ganglionic blockade and reduced affective response. The main actions seem to stem from its potent Dopamine(2) receptor antagonism with minor antagonistic effects on alpha-1 adrenergic receptors as well. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Completely absorbed following intramuscular administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Biphasic distribution. The rapid distribution phase is 1.4 ± 0.5 minutes and the slower distribution phase is 14.3 ± 6.5 minutes. Elimination half-life in adults is 134 ± 13 minutes and may be increased in geriatric patients. In children, it is 101.5 ± 26.4 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The intravenous LD 50 of droperidol is 20-43 mg/kg in mice; 30 mg/kg in rats; 25 mg/kg in dogs and 11-13 mg/kg in rabbits. The intramuscular LD 50 of droperidol is 195 mg/kg in mice, 104-110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs. The manifestations of droperidol overdosage are an extension of its pharmacologic actions. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Inapsine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Droperidol Dropéridol Droperidolo Droperidolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Droperidol is a butyrophenone derivative and dopamine antagonist used to prevent and treat postoperative nausea and vomiting.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Droperidol interact? Information: •Drug A: Buserelin •Drug B: Droperidol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Droperidol. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Droperidol is used to produce tranquilization and to reduce the incidence of nausea and vomiting in surgical and diagnostic procedures. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Droperidol produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness. Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period. Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias, but it does not prevent other cardiac arrhythmias. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanism of action is unknown, however, droperidol causes a CNS depression at subcortical levels of the brain, midbrain, and brainstem reticular formation. It may antagonize the actions of glutamic acid within the extrapyramidal system. It may also inhibit cathecolamine receptors and the reuptake of neurotransmiters and has strong central antidopaminergic action and weak central anticholinergic action. It can also produce ganglionic blockade and reduced affective response. The main actions seem to stem from its potent Dopamine(2) receptor antagonism with minor antagonistic effects on alpha-1 adrenergic receptors as well. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Completely absorbed following intramuscular administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Biphasic distribution. The rapid distribution phase is 1.4 ± 0.5 minutes and the slower distribution phase is 14.3 ± 6.5 minutes. Elimination half-life in adults is 134 ± 13 minutes and may be increased in geriatric patients. In children, it is 101.5 ± 26.4 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The intravenous LD 50 of droperidol is 20-43 mg/kg in mice; 30 mg/kg in rats; 25 mg/kg in dogs and 11-13 mg/kg in rabbits. The intramuscular LD 50 of droperidol is 195 mg/kg in mice, 104-110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs. The manifestations of droperidol overdosage are an extension of its pharmacologic actions. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Inapsine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Droperidol Dropéridol Droperidolo Droperidolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Droperidol is a butyrophenone derivative and dopamine antagonist used to prevent and treat postoperative nausea and vomiting. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dulaglutide interact?

•Drug A: Buserelin •Drug B: Dulaglutide •Severity: MODERATE •Description: The therapeutic efficacy of Dulaglutide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dulaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus. It is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor. This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dulaglutide is slowly absorbed after subcutaneous injection. In a pharmacokinetic study of 20 healthy adults, Cmax occurred within 24-48 hours after dosing. The average absolute bioavailability of dulaglutide after subcutaneous injections of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of dulaglutide was 3.09 L in a pharmacokinetic study; the apparent population mean peripheral volume of distribution was approximately 6 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Protein binding information for dulaglutide is not readily available in the literature. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Elimination of dulaglutide is expected to occur through degradation to individual amino acids. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In a pharmacokinetic study of 20 healthy adults, the average half-life of dulaglutide administered at various doses was approximately 3.75 days (89.9 hours). This extended half-life allows for once-weekly dosing. Prescribing information indicates a half-life of approximately 5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent population mean clearance of dulaglutide was 0.142 L/h in a pharmacokinetic study. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50 information for dulaglutide is not readily available in the literature. Cases of overdose with dulaglutide have resulted in gastrointestinal disturbance. Appropriate supportive treatment is recommended to manage signs and symptoms. Additionally, hypoglycemia has been observed after an overdose with dulaglutide; frequent plasma glucose monitoring should be performed. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Trulicity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dulaglutide is a GLP-1 agonist used to manage type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Dulaglutide interact? Information: •Drug A: Buserelin •Drug B: Dulaglutide •Severity: MODERATE •Description: The therapeutic efficacy of Dulaglutide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dulaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus. It is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor. This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dulaglutide is slowly absorbed after subcutaneous injection. In a pharmacokinetic study of 20 healthy adults, Cmax occurred within 24-48 hours after dosing. The average absolute bioavailability of dulaglutide after subcutaneous injections of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of dulaglutide was 3.09 L in a pharmacokinetic study; the apparent population mean peripheral volume of distribution was approximately 6 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Protein binding information for dulaglutide is not readily available in the literature. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Elimination of dulaglutide is expected to occur through degradation to individual amino acids. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In a pharmacokinetic study of 20 healthy adults, the average half-life of dulaglutide administered at various doses was approximately 3.75 days (89.9 hours). This extended half-life allows for once-weekly dosing. Prescribing information indicates a half-life of approximately 5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent population mean clearance of dulaglutide was 0.142 L/h in a pharmacokinetic study. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50 information for dulaglutide is not readily available in the literature. Cases of overdose with dulaglutide have resulted in gastrointestinal disturbance. Appropriate supportive treatment is recommended to manage signs and symptoms. Additionally, hypoglycemia has been observed after an overdose with dulaglutide; frequent plasma glucose monitoring should be performed. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Trulicity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dulaglutide is a GLP-1 agonist used to manage type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Dyclonine interact?

•Drug A: Buserelin •Drug B: Dyclonine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Dyclonine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used to provide topical anesthesia of accessible mucous membranes prior to examination, endoscopy or instrumentation, or other procedures involving the esophagus, larynx, mouth, pharynx or throat, respiratory tract or trachea, urinary tract, or vagina. Also used to suppress the gag reflex and/or other laryngeal and esophageal reflexes to facilitate dental examination or procedures (including oral surgery), endoscopy, or intubation. Also used for relief of canker sores, cold sores or fever blister. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dyclonine is an oral anasthetic. If substantial quantities of local anesthetics are absorbed through the mucosa, actions on the central nervous system (CNS) may cause CNS stimulation and/or CNS depression. Actions on the cardiovascular system may cause depression of cardiac conduction and excitability and, with some of these agents, peripheral vasodilation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Local anesthetics block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed through mucous membranes into the systemic circulation. The rate of absorption is influenced by the vascularity or rate of blood flow at the site of application, the total dosage (concentration and volume) administered, and the duration of exposure. Absorption from mucous membranes of the throat or respiratory tract may be especially rapid. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Approximately 30 to 60 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include cardiovascular system depression, CNS toxicity, and methemoglobinemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Dyclopro, Sucrets •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Diclonina Dyclocaine Dyclonin Dyclonine Dycloninum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dyclonine is an topical anesthetic used prior to examination to suppress the gag reflex or for pain relief from canker sores and fever blisters.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Dyclonine interact? Information: •Drug A: Buserelin •Drug B: Dyclonine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Dyclonine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used to provide topical anesthesia of accessible mucous membranes prior to examination, endoscopy or instrumentation, or other procedures involving the esophagus, larynx, mouth, pharynx or throat, respiratory tract or trachea, urinary tract, or vagina. Also used to suppress the gag reflex and/or other laryngeal and esophageal reflexes to facilitate dental examination or procedures (including oral surgery), endoscopy, or intubation. Also used for relief of canker sores, cold sores or fever blister. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dyclonine is an oral anasthetic. If substantial quantities of local anesthetics are absorbed through the mucosa, actions on the central nervous system (CNS) may cause CNS stimulation and/or CNS depression. Actions on the cardiovascular system may cause depression of cardiac conduction and excitability and, with some of these agents, peripheral vasodilation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Local anesthetics block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed through mucous membranes into the systemic circulation. The rate of absorption is influenced by the vascularity or rate of blood flow at the site of application, the total dosage (concentration and volume) administered, and the duration of exposure. Absorption from mucous membranes of the throat or respiratory tract may be especially rapid. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Approximately 30 to 60 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include cardiovascular system depression, CNS toxicity, and methemoglobinemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Dyclopro, Sucrets •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Diclonina Dyclocaine Dyclonin Dyclonine Dycloninum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dyclonine is an topical anesthetic used prior to examination to suppress the gag reflex or for pain relief from canker sores and fever blisters. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Ebastine interact?

•Drug A: Buserelin •Drug B: Ebastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ebastine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ebastine is a second generation H1-receptor antagonist useful in the treatment of allergic rhinitis and urticaria.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ebastine interact? Information: •Drug A: Buserelin •Drug B: Ebastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ebastine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ebastine is a second generation H1-receptor antagonist useful in the treatment of allergic rhinitis and urticaria. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Efavirenz interact?

•Drug A: Buserelin •Drug B: Efavirenz •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Efavirenz. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use in combination treatment of HIV infection (AIDS) •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 99.5-99.75% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 40-55 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Atripla, Stocrin, Sustiva, Symfi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Efavirenz Éfavirenz Efavirenzum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Efavirenz is a non-nucleoside reverse transcriptase inhibitor used to treat HIV infection or prevent the spread of HIV.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Efavirenz interact? Information: •Drug A: Buserelin •Drug B: Efavirenz •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Efavirenz. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use in combination treatment of HIV infection (AIDS) •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 99.5-99.75% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 40-55 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Atripla, Stocrin, Sustiva, Symfi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Efavirenz Éfavirenz Efavirenzum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Efavirenz is a non-nucleoside reverse transcriptase inhibitor used to treat HIV infection or prevent the spread of HIV. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Eliglustat interact?

•Drug A: Buserelin •Drug B: Eliglustat •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Eliglustat. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Eliglustat is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease in adult patients who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. CYP2D6 ultra-rapid metabolizers may not achieve adequate eliglustat concentrations to achieve a therapeutic effect. A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Eliglustat is a specific inhibitor of glucosylceramide synthase (IC 50 =10 ng/mL). In vitro studies suggest that eliglustat has minimal or no off-target activity against other glycosidases, such as α-glucosidase I and II, and lysosomal and non-lysosomal glucosylceramidases. At 8 times the recommended dose (800 mg) and a ​​mean peak concentration of 237 ng/mL, eliglustat did not have a clinically significant effect on QTc prolongation. However, modelling of PK/PD data predicts that at a plasma concentration of 500 ng/mL, PR, QRS and QTcF intervals increase 22, 7, and 13 msec, respectively. Since high plasma concentrations of eliglustat may increase the risk of cardiac arrhythmias, there are warnings and precautions for patients taking CYP2D6 or CYP3A4 inhibitors, those with specific CYP2D6 metabolizer status and different degrees of hepatic impairment. Depending on each case, the use of this drug is contraindicated, to be avoided, or requires dosage adjustment. Patients with preexisting cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, or those taking Class IA or Class II antiarrhythmic drugs are advised to avoid eliglustat. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Eliglustat is a glucosylceramide synthase inhibitor used for the treatment of type 1 Gaucher disease. Gaucher disease is a rare genetic disorder characterized by the deficiency of acid β-glucosidase, an enzyme that converts glucosylceramide (also known as glucocerebroside) into glucose and ceramide. In patients with Gaucher disease, glucosylceramide is accumulated in the lysosomes of macrophages, leading to the formation of foam cells or Gaucher cells. Gaucher cells infiltrate the liver, spleen, bone marrow and other organs, leading to complications such as anemia, thrombocytopenia and hepatosplenomegaly. Eliglustat reduces the production of glucosylceramide by inhibiting glucosylceramide synthase, a rate-limiting enzyme in the production of glycosphingolipids. This lowers the amount of glucosylceramide that is available in lysosomes, and balances the deficiency of acid β-glucosidase. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Eliglustat administered in multiple doses of 84 mg twice daily had a C max of 12.1 to 25.0 ng/mL in CYP2D6 extensive metabolizers (EMs), 44.6 ng/mL in CYP2D6 intermediate metabolizers (IMs), and 113 to 137 ng/mL in CYP2D6 poor metabolizers (PMs). The median T max was 1.5-2 hr in CYP2D6 EMs, 2 hr in CYP2D6 IMs, and 3 hr in CYP2D6 PMs. The AUC tau was 76.3-143 ng∙hr/mL in CYP2D6 EMs, 306 ng∙hr/mL in CYP2D6 IMs, and 922-1057 ng∙hr/mL in CYP2D6 PMs. In CYP2D6 EMs, the pharmacokinetics of eliglustat is time-dependent, and for doses that range between 42 and 294 mg, exposure increases in a more than dose-proportional fashion. In CYP2D6 PMs, eliglustat pharmacokinetics is linear and time-independent. In a steady state, the systemic exposure of 84 mg eliglustat twice daily is 7- to 9-fold higher in CYP2D6 PMs compared to EMs. Following the oral administration of a single 84 mg dose of eliglustat, bioavailability in CYP2D6 EMs was lower than 5%. The low oral bioavailability of eliglustat suggests the role of transporters and/or an extensive first-pass metabolism. Eliglustat can be taken with or without food. In CYP2D6 EMs, severe renal impairment did not have an effect on eliglustat pharmacokinetics. The effect of renal impairment on eliglustat pharmacokinetics was not evaluated in CYP2D6 IMs, CYP2D6 PMs or CYP2D6 EMs with end-stage renal failure. Compared to CYP2D6 EMs with normal hepatic function, C max and AUC were 1.2-fold higher in CYP2D6 EMs with mild hepatic impairment, while C max and AUC were 2.8- and 5.2-fold higher, respectively, in CYP2D6 EMs with moderate hepatic impairment. The effect of mild and moderate hepatic impairment in CYP2D6 IMs and PMs, and the effect of severe hepatic impairment were not evaluated. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In CYP2D6 extensive metabolizers (EM), the volume of distribution of eliglustat administered IV was 835 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): In plasma, the protein binding of eliglustat goes from 76% to 83%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Eliglustat is mostly metabolized by CYP2D6, and to a lower extent, by CYP3A4. In patients that are CYP2D6 poor metabolizers (PMs), eliglustat is mainly metabolized by CYP3A4. The primary metabolic pathways of eliglustat involve the sequential oxidation of the octanoyl moiety and the 2,3-dihydro-1,4-benzodioxane moiety. The combination of these two pathways results in the production of several oxidative metabolites. After evaluating the potency of eliglustat metabolites, it was determined that none of them were active. Genz-399240 (M24) was identified as the major metabolite of eliglustat, while the rest of the metabolites contributed to less than 10% of total drug-related exposures. Genz-399240 (M24) did not show any major off-target effects; therefore, a transporter substrate specificity characterization was not performed. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Eliglustat is mainly excreted in urine (42%) and feces (51%) as metabolites after oral administration. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Eliglustat has a terminal elimination half-life of 6.5 hours in CYP2D6 extensive metabolizers (EMs) and 8.9 h in CYP2D6 poor metabolizers (PMs). •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy CYP2D6 extensive metabolizers (EMs) administered 42 mg of eliglustat IV (0.5 times the recommended oral dose), clearance was 88 L/h (80-105 L/h). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Eliglustat overdose may manifest as dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting. These symptoms were detected in a healthy subject taking 21-times the dose recommended to type 1 Gaucher disease patients. Eliglustat has no known antidote. In case of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment. Due to the large volume of distribution of eliglustat, hemodialysis is not likely to be beneficial. Acute dose toxicity studies were performed in rats and dogs. In rats, the maximum tolerated dose was 200 mg/kg, and in non-fasted dogs, the maximum tolerated dose was 25 mg/kg. Some of the adverse effects detected in these toxicity studies manifested on the GI tract, hematology parameters related to hemoglobin and coagulation process, reproductive organs, thymus and other lymphoid organs. Adverse effects in the kidney and liver were only detected in rats. Carcinogenic studies were performed in both Sprague-Dawley rats and CD-1 mice. In doses up to 50 mg/kg/day in female Sprague-Dawley rats and 75 mg/kg/day in male Sprague-Dawley rats and CD-1 mice, eliglustat did not induce neoplasms. Eliglustat was negative in the following mutagenesis tests: Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cerdelga •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Eliglustat éliglustat Eliglustatum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Eliglustat is a glucosylceramide synthase used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Eliglustat interact? Information: •Drug A: Buserelin •Drug B: Eliglustat •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Eliglustat. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Eliglustat is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease in adult patients who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. CYP2D6 ultra-rapid metabolizers may not achieve adequate eliglustat concentrations to achieve a therapeutic effect. A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Eliglustat is a specific inhibitor of glucosylceramide synthase (IC 50 =10 ng/mL). In vitro studies suggest that eliglustat has minimal or no off-target activity against other glycosidases, such as α-glucosidase I and II, and lysosomal and non-lysosomal glucosylceramidases. At 8 times the recommended dose (800 mg) and a ​​mean peak concentration of 237 ng/mL, eliglustat did not have a clinically significant effect on QTc prolongation. However, modelling of PK/PD data predicts that at a plasma concentration of 500 ng/mL, PR, QRS and QTcF intervals increase 22, 7, and 13 msec, respectively. Since high plasma concentrations of eliglustat may increase the risk of cardiac arrhythmias, there are warnings and precautions for patients taking CYP2D6 or CYP3A4 inhibitors, those with specific CYP2D6 metabolizer status and different degrees of hepatic impairment. Depending on each case, the use of this drug is contraindicated, to be avoided, or requires dosage adjustment. Patients with preexisting cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, or those taking Class IA or Class II antiarrhythmic drugs are advised to avoid eliglustat. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Eliglustat is a glucosylceramide synthase inhibitor used for the treatment of type 1 Gaucher disease. Gaucher disease is a rare genetic disorder characterized by the deficiency of acid β-glucosidase, an enzyme that converts glucosylceramide (also known as glucocerebroside) into glucose and ceramide. In patients with Gaucher disease, glucosylceramide is accumulated in the lysosomes of macrophages, leading to the formation of foam cells or Gaucher cells. Gaucher cells infiltrate the liver, spleen, bone marrow and other organs, leading to complications such as anemia, thrombocytopenia and hepatosplenomegaly. Eliglustat reduces the production of glucosylceramide by inhibiting glucosylceramide synthase, a rate-limiting enzyme in the production of glycosphingolipids. This lowers the amount of glucosylceramide that is available in lysosomes, and balances the deficiency of acid β-glucosidase. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Eliglustat administered in multiple doses of 84 mg twice daily had a C max of 12.1 to 25.0 ng/mL in CYP2D6 extensive metabolizers (EMs), 44.6 ng/mL in CYP2D6 intermediate metabolizers (IMs), and 113 to 137 ng/mL in CYP2D6 poor metabolizers (PMs). The median T max was 1.5-2 hr in CYP2D6 EMs, 2 hr in CYP2D6 IMs, and 3 hr in CYP2D6 PMs. The AUC tau was 76.3-143 ng∙hr/mL in CYP2D6 EMs, 306 ng∙hr/mL in CYP2D6 IMs, and 922-1057 ng∙hr/mL in CYP2D6 PMs. In CYP2D6 EMs, the pharmacokinetics of eliglustat is time-dependent, and for doses that range between 42 and 294 mg, exposure increases in a more than dose-proportional fashion. In CYP2D6 PMs, eliglustat pharmacokinetics is linear and time-independent. In a steady state, the systemic exposure of 84 mg eliglustat twice daily is 7- to 9-fold higher in CYP2D6 PMs compared to EMs. Following the oral administration of a single 84 mg dose of eliglustat, bioavailability in CYP2D6 EMs was lower than 5%. The low oral bioavailability of eliglustat suggests the role of transporters and/or an extensive first-pass metabolism. Eliglustat can be taken with or without food. In CYP2D6 EMs, severe renal impairment did not have an effect on eliglustat pharmacokinetics. The effect of renal impairment on eliglustat pharmacokinetics was not evaluated in CYP2D6 IMs, CYP2D6 PMs or CYP2D6 EMs with end-stage renal failure. Compared to CYP2D6 EMs with normal hepatic function, C max and AUC were 1.2-fold higher in CYP2D6 EMs with mild hepatic impairment, while C max and AUC were 2.8- and 5.2-fold higher, respectively, in CYP2D6 EMs with moderate hepatic impairment. The effect of mild and moderate hepatic impairment in CYP2D6 IMs and PMs, and the effect of severe hepatic impairment were not evaluated. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In CYP2D6 extensive metabolizers (EM), the volume of distribution of eliglustat administered IV was 835 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): In plasma, the protein binding of eliglustat goes from 76% to 83%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Eliglustat is mostly metabolized by CYP2D6, and to a lower extent, by CYP3A4. In patients that are CYP2D6 poor metabolizers (PMs), eliglustat is mainly metabolized by CYP3A4. The primary metabolic pathways of eliglustat involve the sequential oxidation of the octanoyl moiety and the 2,3-dihydro-1,4-benzodioxane moiety. The combination of these two pathways results in the production of several oxidative metabolites. After evaluating the potency of eliglustat metabolites, it was determined that none of them were active. Genz-399240 (M24) was identified as the major metabolite of eliglustat, while the rest of the metabolites contributed to less than 10% of total drug-related exposures. Genz-399240 (M24) did not show any major off-target effects; therefore, a transporter substrate specificity characterization was not performed. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Eliglustat is mainly excreted in urine (42%) and feces (51%) as metabolites after oral administration. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Eliglustat has a terminal elimination half-life of 6.5 hours in CYP2D6 extensive metabolizers (EMs) and 8.9 h in CYP2D6 poor metabolizers (PMs). •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy CYP2D6 extensive metabolizers (EMs) administered 42 mg of eliglustat IV (0.5 times the recommended oral dose), clearance was 88 L/h (80-105 L/h). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Eliglustat overdose may manifest as dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting. These symptoms were detected in a healthy subject taking 21-times the dose recommended to type 1 Gaucher disease patients. Eliglustat has no known antidote. In case of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment. Due to the large volume of distribution of eliglustat, hemodialysis is not likely to be beneficial. Acute dose toxicity studies were performed in rats and dogs. In rats, the maximum tolerated dose was 200 mg/kg, and in non-fasted dogs, the maximum tolerated dose was 25 mg/kg. Some of the adverse effects detected in these toxicity studies manifested on the GI tract, hematology parameters related to hemoglobin and coagulation process, reproductive organs, thymus and other lymphoid organs. Adverse effects in the kidney and liver were only detected in rats. Carcinogenic studies were performed in both Sprague-Dawley rats and CD-1 mice. In doses up to 50 mg/kg/day in female Sprague-Dawley rats and 75 mg/kg/day in male Sprague-Dawley rats and CD-1 mice, eliglustat did not induce neoplasms. Eliglustat was negative in the following mutagenesis tests: Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cerdelga •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Eliglustat éliglustat Eliglustatum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Eliglustat is a glucosylceramide synthase used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Emedastine interact?

•Drug A: Buserelin •Drug B: Emedastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Emedastine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the temporary relief of the signs and symptoms of allergic conjunctivitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Emedastine is a relatively selective H 1 -receptor antagonist. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Emedastine is a relatively selective, histamine H 1 antagonist. In vitro examinations of emedastine's affinity for histamine receptors demonstrate relative selectivity for the H 1 histamine receptor. In vivo studies have shown concentration-dependent inhibition of histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Emedastine appears exert negligible effects on adrenergic, dopaminergic and serotonin receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Ophthalmic use of emedastine usually does not produce measurable plasma concentrations. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Two primary metabolites, 5-hydroxyemedastine and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. Minor metabolites include the 5'-oxoanalogs of 5-hydroxyemedastine and 6-hydroxy-emedastine and the N-oxide. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration, approximately 44% of the total dose can be recovered in the urine over the 24-hour period, with only 3.6% of the dose excreted as unchanged form. Two primary metabolites, 5- and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life in the plasma is 3-4 hours following oral administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Somnolence and malaise have been reported following daily oral administration. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Emadine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Emedastina Emedastine Emedastinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Emedastine is a selective H1-receptor antagonist used topically to manage symptoms of allergic conjunctivitis.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Emedastine interact? Information: •Drug A: Buserelin •Drug B: Emedastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Emedastine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the temporary relief of the signs and symptoms of allergic conjunctivitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Emedastine is a relatively selective H 1 -receptor antagonist. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Emedastine is a relatively selective, histamine H 1 antagonist. In vitro examinations of emedastine's affinity for histamine receptors demonstrate relative selectivity for the H 1 histamine receptor. In vivo studies have shown concentration-dependent inhibition of histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Emedastine appears exert negligible effects on adrenergic, dopaminergic and serotonin receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Ophthalmic use of emedastine usually does not produce measurable plasma concentrations. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Two primary metabolites, 5-hydroxyemedastine and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. Minor metabolites include the 5'-oxoanalogs of 5-hydroxyemedastine and 6-hydroxy-emedastine and the N-oxide. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration, approximately 44% of the total dose can be recovered in the urine over the 24-hour period, with only 3.6% of the dose excreted as unchanged form. Two primary metabolites, 5- and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life in the plasma is 3-4 hours following oral administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Somnolence and malaise have been reported following daily oral administration. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Emadine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Emedastina Emedastine Emedastinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Emedastine is a selective H1-receptor antagonist used topically to manage symptoms of allergic conjunctivitis. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Empagliflozin interact?

•Drug A: Buserelin •Drug B: Empagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Empagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years and older with type 2 diabetes. It is used either alone or in combination with metformin or linagliptin. It is also indicated to reduce the risk of cardiovascular death in adult patients with both type 2 diabetes mellitus and established cardiovascular disease, either alone or as a combination product with metformin. An extended-release combination product containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. Empagliflozin is also approved to reduce the risk of cardiovascular mortality and hospitalization due to heart failure in adult patients with heart failure, either alone or in combination with metformin. It is also indicated in adults to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. Empagliflozin is not approved for use in patients with type 1 diabetes. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na /K -ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na /H exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, peak plasma concentrations are reached in approximately 1.5 hours (T max ). At steady-state, plasma AUC and C max were 1870 nmol·h/L and 259 nmol/L, respectively, following therapy with empagliflozin 10mg daily and 4740 nmol·h/L and 687 nmol/L, respectively, following therapy with empagliflozin 25mg daily. Administration with food does not significantly affect the absorption of empagliflozin. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The estimated apparent steady-state volume of distribution is 73.8 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Empagliflozin is approximately 86.2% protein-bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Empagliflozin undergoes minimal metabolism. It is primarily metabolized via glucuronidation by 5'-diphospho-glucuronosyltransferases 2B7, 1A3, 1A8, and 1A9 to yield three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. No metabolite represented more than 10% of total drug-related material. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After oral administration of radiolabeled empagliflozin approximately 41.2% of the administered dose was found eliminated in feces and 54.4% eliminated in urine. The majority of radioactivity in the feces was due to unchanged parent drug while approximately half of the radioactivity in urine was due to unchanged parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The apparent terminal elimination half-life was found to be 12.4 h based on population pharmacokinetic analysis. •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent oral clearance was found to be 10.6 L/h based on a population pharmacokinetic analysis. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Experience with empagliflozin overdose is limited - employ standard symptomatic and supportive measures, as well as gastric decontamination when appropriate. The use of hemodialysis in empagliflozin overdose has not been studied but is unlikely to be of benefit given the drug's relatively high protein-binding. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Glyxambi, Jardiance, Synjardy, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Empagliflozin Empagliflozina Empagliflozine Empagliflozinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Empagliflozin is an SGLT2 inhibitor used to manage type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Empagliflozin interact? Information: •Drug A: Buserelin •Drug B: Empagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Empagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years and older with type 2 diabetes. It is used either alone or in combination with metformin or linagliptin. It is also indicated to reduce the risk of cardiovascular death in adult patients with both type 2 diabetes mellitus and established cardiovascular disease, either alone or as a combination product with metformin. An extended-release combination product containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. Empagliflozin is also approved to reduce the risk of cardiovascular mortality and hospitalization due to heart failure in adult patients with heart failure, either alone or in combination with metformin. It is also indicated in adults to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. Empagliflozin is not approved for use in patients with type 1 diabetes. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na /K -ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na /H exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, peak plasma concentrations are reached in approximately 1.5 hours (T max ). At steady-state, plasma AUC and C max were 1870 nmol·h/L and 259 nmol/L, respectively, following therapy with empagliflozin 10mg daily and 4740 nmol·h/L and 687 nmol/L, respectively, following therapy with empagliflozin 25mg daily. Administration with food does not significantly affect the absorption of empagliflozin. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The estimated apparent steady-state volume of distribution is 73.8 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Empagliflozin is approximately 86.2% protein-bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Empagliflozin undergoes minimal metabolism. It is primarily metabolized via glucuronidation by 5'-diphospho-glucuronosyltransferases 2B7, 1A3, 1A8, and 1A9 to yield three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. No metabolite represented more than 10% of total drug-related material. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After oral administration of radiolabeled empagliflozin approximately 41.2% of the administered dose was found eliminated in feces and 54.4% eliminated in urine. The majority of radioactivity in the feces was due to unchanged parent drug while approximately half of the radioactivity in urine was due to unchanged parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The apparent terminal elimination half-life was found to be 12.4 h based on population pharmacokinetic analysis. •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent oral clearance was found to be 10.6 L/h based on a population pharmacokinetic analysis. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Experience with empagliflozin overdose is limited - employ standard symptomatic and supportive measures, as well as gastric decontamination when appropriate. The use of hemodialysis in empagliflozin overdose has not been studied but is unlikely to be of benefit given the drug's relatively high protein-binding. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Glyxambi, Jardiance, Synjardy, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Empagliflozin Empagliflozina Empagliflozine Empagliflozinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Empagliflozin is an SGLT2 inhibitor used to manage type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Encorafenib interact?

•Drug A: Buserelin •Drug B: Encorafenib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Encorafenib is combined with Buserelin. •Extended Description: QT prolongation is a known side effect associated with BRAF inhibitors, although the exact mechanism is unknown.1,3 Therefore, the concomitant use of encorafenib with a QT prolonging agent can have an additive effect, further exacerbating QT prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Encorafenib is indicated in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Encorafenib has a pharmacologic profile that is distinct from that of other clinically active BRAF inhibitors and has shown improved efficacy in the treatment of metastatic melanoma. Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma. Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, the co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the co-administration compared to either drug alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. The co-administration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36, and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 µM). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was dose-proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose-proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. After oral administration, the median T max of encorafenib is 2 hours. At least 86% of the dose is absorbed. Following administration of a single dose of encorafenib 100 mg (0.2 times the maximum recommended dose of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (C max ) decreased by 36% and there was no effect on AUC. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). •Protein binding (Drug A): 15% •Protein binding (Drug B): Encorafenib is 86% bound to human plasma proteins in vitro. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean (CV%) terminal half-life (t 1/2 ) of encorafenib is 3.5 hours (17%). •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib. In COLUMBUS, a phase 3 safety and efficacy trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. The median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months). Tumor promotion in BRAF Wild-Type Tumors has been observed with encofarenib use. Hemorrhage, uveitis, QT interval prolongation are also other adverse events observed while taking this medication. Encorafenib, when used as a single agent, is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI therapy alone compared to 2% of patients treated with BRAFTOVI in combination with binimetinib. Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats. No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies. Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Braftovi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Encorafenib is a kinase inhibitor used to treat unresectable or metastatic melanoma with specific mutations.

QT prolongation is a known side effect associated with BRAF inhibitors, although the exact mechanism is unknown.1,3 Therefore, the concomitant use of encorafenib with a QT prolonging agent can have an additive effect, further exacerbating QT prolongation. The severity of the interaction is moderate.

Question: Does Buserelin and Encorafenib interact? Information: •Drug A: Buserelin •Drug B: Encorafenib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Encorafenib is combined with Buserelin. •Extended Description: QT prolongation is a known side effect associated with BRAF inhibitors, although the exact mechanism is unknown.1,3 Therefore, the concomitant use of encorafenib with a QT prolonging agent can have an additive effect, further exacerbating QT prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Encorafenib is indicated in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Encorafenib has a pharmacologic profile that is distinct from that of other clinically active BRAF inhibitors and has shown improved efficacy in the treatment of metastatic melanoma. Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma. Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, the co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the co-administration compared to either drug alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. The co-administration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36, and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 µM). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was dose-proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose-proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. After oral administration, the median T max of encorafenib is 2 hours. At least 86% of the dose is absorbed. Following administration of a single dose of encorafenib 100 mg (0.2 times the maximum recommended dose of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (C max ) decreased by 36% and there was no effect on AUC. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). •Protein binding (Drug A): 15% •Protein binding (Drug B): Encorafenib is 86% bound to human plasma proteins in vitro. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean (CV%) terminal half-life (t 1/2 ) of encorafenib is 3.5 hours (17%). •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib. In COLUMBUS, a phase 3 safety and efficacy trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. The median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months). Tumor promotion in BRAF Wild-Type Tumors has been observed with encofarenib use. Hemorrhage, uveitis, QT interval prolongation are also other adverse events observed while taking this medication. Encorafenib, when used as a single agent, is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI therapy alone compared to 2% of patients treated with BRAFTOVI in combination with binimetinib. Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats. No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies. Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Braftovi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Encorafenib is a kinase inhibitor used to treat unresectable or metastatic melanoma with specific mutations. Output: QT prolongation is a known side effect associated with BRAF inhibitors, although the exact mechanism is unknown.1,3 Therefore, the concomitant use of encorafenib with a QT prolonging agent can have an additive effect, further exacerbating QT prolongation. The severity of the interaction is moderate.

Does Buserelin and Enoxacin interact?

•Drug A: Buserelin •Drug B: Enoxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Enoxacin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of adults (≥18 years of age) with the following infections caused by susceptible strains of the designated microorganisms: (1) uncomplicated urethral or cervical gonorrhea due to Neisseria gonorrhoeae, (2) uncomplicated urinary tract infections (cystitis) due to Escherichia coli, Staphylococcus epidermidis, or Staphylococcus saprophyticus, and (3) complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, or Enterobacter cloacae. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Enoxacin is a quinolone/fluoroquinolone antibiotic. Enoxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Enoxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. Enoxacin may be active against pathogens resistant to drugs that act by different mechanisms. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Enoxacin exerts its bactericidal action via the inhibition of the essential bacterial enzyme DNA gyrase (DNA Topoisomerase II). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration, with an absolute oral bioavailability of approximately 90%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Enoxacin is approximately 40% bound to plasma proteins in healthy subjects and is approximately 14% bound to plasma proteins in patients with impaired renal function. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Some isozymes of the cytochrome P-450 hepatic microsomal enzyme system are inhibited by enoxacin. After a single dose, greater than 40% was recovered in urine by 48 hours as unchanged drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Plasma half-life is 3 to 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Enoxacin Enoxacina Énoxacine Enoxacino Enoxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): No summary available

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Enoxacin interact? Information: •Drug A: Buserelin •Drug B: Enoxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Enoxacin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of adults (≥18 years of age) with the following infections caused by susceptible strains of the designated microorganisms: (1) uncomplicated urethral or cervical gonorrhea due to Neisseria gonorrhoeae, (2) uncomplicated urinary tract infections (cystitis) due to Escherichia coli, Staphylococcus epidermidis, or Staphylococcus saprophyticus, and (3) complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, or Enterobacter cloacae. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Enoxacin is a quinolone/fluoroquinolone antibiotic. Enoxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Enoxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. Enoxacin may be active against pathogens resistant to drugs that act by different mechanisms. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Enoxacin exerts its bactericidal action via the inhibition of the essential bacterial enzyme DNA gyrase (DNA Topoisomerase II). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration, with an absolute oral bioavailability of approximately 90%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Enoxacin is approximately 40% bound to plasma proteins in healthy subjects and is approximately 14% bound to plasma proteins in patients with impaired renal function. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Some isozymes of the cytochrome P-450 hepatic microsomal enzyme system are inhibited by enoxacin. After a single dose, greater than 40% was recovered in urine by 48 hours as unchanged drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Plasma half-life is 3 to 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Enoxacin Enoxacina Énoxacine Enoxacino Enoxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): No summary available Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Entrectinib interact?

•Drug A: Buserelin •Drug B: Entrectinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Entrectinib. •Extended Description: Entrectinib is known to produce Qtc-interval prolongation.2,1 Concomitant use of entrectinib with other QTc-prolonging agents may produce and additive or synergistic increase in the risk of torsades de pointes. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults. Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available. FoundationOne®Liquid CDx is the only FDA-approved test for the detection of ROS1 rearrangement(s) in NSCLC for selecting patients for treatment with entrectinib. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation. This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-γ. ALK produces similar signalling with the addition of downstream JAK/STAT activation. Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose. Food does not produce a significant effect on the extent of absorption. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Entrectinib has an apparent volume of distribution of 551 L. The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): Entrectinib is over 99% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5. M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine. Of the dose in the feces, 36% was present as entrectinib and 22% as M5. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Entrectinib has a half-life of elimination of 20 h. The active metabolite, M5, has a half-life of 40 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rozlytrek •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): No summary available

Entrectinib is known to produce Qtc-interval prolongation.2,1 Concomitant use of entrectinib with other QTc-prolonging agents may produce and additive or synergistic increase in the risk of torsades de pointes. The severity of the interaction is moderate.

Question: Does Buserelin and Entrectinib interact? Information: •Drug A: Buserelin •Drug B: Entrectinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Entrectinib. •Extended Description: Entrectinib is known to produce Qtc-interval prolongation.2,1 Concomitant use of entrectinib with other QTc-prolonging agents may produce and additive or synergistic increase in the risk of torsades de pointes. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults. Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available. FoundationOne®Liquid CDx is the only FDA-approved test for the detection of ROS1 rearrangement(s) in NSCLC for selecting patients for treatment with entrectinib. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation. This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-γ. ALK produces similar signalling with the addition of downstream JAK/STAT activation. Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose. Food does not produce a significant effect on the extent of absorption. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Entrectinib has an apparent volume of distribution of 551 L. The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): Entrectinib is over 99% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5. M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine. Of the dose in the feces, 36% was present as entrectinib and 22% as M5. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Entrectinib has a half-life of elimination of 20 h. The active metabolite, M5, has a half-life of 40 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rozlytrek •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): No summary available Output: Entrectinib is known to produce Qtc-interval prolongation.2,1 Concomitant use of entrectinib with other QTc-prolonging agents may produce and additive or synergistic increase in the risk of torsades de pointes. The severity of the interaction is moderate.

Does Buserelin and Epinastine interact?

•Drug A: Buserelin •Drug B: Epinastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Epinastine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the prevention of itching associated with allergic conjunctivitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Epinastine is an antihistamine and an inhibitor of histamine release from the mast cell for topical administration to the eyes. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. Epinastine is a topically active, direct H 1 -receptor antagonist and an inhibitor of the release of histamine from the mast cell. Epinastine is selective for the histamine H 1 -receptor and has affinity for the histamine H2 receptor. Epinastine also possesses affinity for the a1-, a2-, and 5-HT 2 -receptors. Epinastine does not penetrate the blood/brain barrier and, therefore, is not expected to induce side effects of the central nervous system. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Epinastine has a multiaction effect that inhibits the allergic response in 3 ways: 1. stabilizes mast cells by preventing mast cell degranulation to control the allergic response, 2. prevents histamine binding to both the H1- and H 2 -receptors to stop itching and provide lasting protection, and 3. prevents the release of proinflammatory chemical mediators from the blood vessel to halt progression of the allergic response. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absolute bioavailability of epinastine is about 40%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 64% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Mainly excreted unchanged, less than 10% metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Epinastine is mainly excreted unchanged. The renal elimination is mainly via active tubular secretion. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 56 L/hr [patients with allergic conjunctivitis receiving one drop of ELESTAT® ophthalmic solution in each eye twice daily for seven days] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Elestat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epinastin Epinastina Epinastine épinastine Epinastinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Epinastine is an H1 receptor antagonist used to prevent itching in allergic conjunctivitis.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Epinastine interact? Information: •Drug A: Buserelin •Drug B: Epinastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Epinastine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the prevention of itching associated with allergic conjunctivitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Epinastine is an antihistamine and an inhibitor of histamine release from the mast cell for topical administration to the eyes. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. Epinastine is a topically active, direct H 1 -receptor antagonist and an inhibitor of the release of histamine from the mast cell. Epinastine is selective for the histamine H 1 -receptor and has affinity for the histamine H2 receptor. Epinastine also possesses affinity for the a1-, a2-, and 5-HT 2 -receptors. Epinastine does not penetrate the blood/brain barrier and, therefore, is not expected to induce side effects of the central nervous system. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Epinastine has a multiaction effect that inhibits the allergic response in 3 ways: 1. stabilizes mast cells by preventing mast cell degranulation to control the allergic response, 2. prevents histamine binding to both the H1- and H 2 -receptors to stop itching and provide lasting protection, and 3. prevents the release of proinflammatory chemical mediators from the blood vessel to halt progression of the allergic response. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absolute bioavailability of epinastine is about 40%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 64% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Mainly excreted unchanged, less than 10% metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Epinastine is mainly excreted unchanged. The renal elimination is mainly via active tubular secretion. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 56 L/hr [patients with allergic conjunctivitis receiving one drop of ELESTAT® ophthalmic solution in each eye twice daily for seven days] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Elestat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epinastin Epinastina Epinastine épinastine Epinastinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Epinastine is an H1 receptor antagonist used to prevent itching in allergic conjunctivitis. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Eribulin interact?

•Drug A: Buserelin •Drug B: Eribulin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Eribulin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic cancer. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Linear •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. [FDA] •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 43 L/m2 to 114 L/m2 •Protein binding (Drug A): 15% •Protein binding (Drug B): 49 to 65%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): There are no major human metabolites of eribulin, CYP3A4 negligibly metabolizes eribulin in vitro. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Eribulin is eliminated primarily in feces unchanged. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): about 40 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 1.16 L/hr/m2 to 2.42 L/hr/m2 (dose range of 0.25 mg/m2 to 4.0 mg/m2). [FDA] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin (5 percent). [Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.] Single doses of 0.75 mg/kg were lethal to rats and two doses of 0.075 mg/kg were lethal to dogs. The no-observed-adverse-effect level (NOAEL) in rats and dogs were 0.015 and 0.0045 mg/kg/day, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Halaven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Eribulin is a microtubule inhibitor used to treat metastatic breast cancer and metastatic or unresectable liposarcoma.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Eribulin interact? Information: •Drug A: Buserelin •Drug B: Eribulin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Eribulin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic cancer. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Linear •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. [FDA] •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 43 L/m2 to 114 L/m2 •Protein binding (Drug A): 15% •Protein binding (Drug B): 49 to 65%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): There are no major human metabolites of eribulin, CYP3A4 negligibly metabolizes eribulin in vitro. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Eribulin is eliminated primarily in feces unchanged. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): about 40 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 1.16 L/hr/m2 to 2.42 L/hr/m2 (dose range of 0.25 mg/m2 to 4.0 mg/m2). [FDA] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin (5 percent). [Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.] Single doses of 0.75 mg/kg were lethal to rats and two doses of 0.075 mg/kg were lethal to dogs. The no-observed-adverse-effect level (NOAEL) in rats and dogs were 0.015 and 0.0045 mg/kg/day, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Halaven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Eribulin is a microtubule inhibitor used to treat metastatic breast cancer and metastatic or unresectable liposarcoma. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Erlotinib interact?

•Drug A: Buserelin •Drug B: Erlotinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Erlotinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Erlotinib is indicated for: The treatment of metastatic non-small cell lung cancer (NSCLC) with tumors showing epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. In combination with first-line treatment for patients diagnosed with locally advanced, unresectable or metastatic pancreatic cancer. The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Apparent volume of distribution = 232 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG) •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Median half-life of 36.2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Smokers have a 24% higher rate of erlotinib clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tarceva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Erlotinib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Erlotinib is an EGFR tyrosine kinase inhibitor used to treat certain small cell lung cancers or advanced metastatic pancreatic cancers.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Erlotinib interact? Information: •Drug A: Buserelin •Drug B: Erlotinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Erlotinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Erlotinib is indicated for: The treatment of metastatic non-small cell lung cancer (NSCLC) with tumors showing epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. In combination with first-line treatment for patients diagnosed with locally advanced, unresectable or metastatic pancreatic cancer. The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Apparent volume of distribution = 232 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG) •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Median half-life of 36.2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Smokers have a 24% higher rate of erlotinib clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tarceva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Erlotinib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Erlotinib is an EGFR tyrosine kinase inhibitor used to treat certain small cell lung cancers or advanced metastatic pancreatic cancers. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Ertugliflozin interact?

•Drug A: Buserelin •Drug B: Ertugliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Ertugliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ertugliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus (T2DM). It is also available in combination with either metformin or sitagliptin. Ertugliflozin is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ertugliflozin causes a dose-dependent increase in urinary glucose excretion and an increase in urinary volume in patients with T2DM. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Kidneys play an integral role in glucose homeostasis. After being filtered into urine within the nephron, most of the plasma glucose is reabsorbed through two types of sodium-dependent glucose cotransporters (SGLTs), SGLT1 and SGLT2, expressed in proximal renal tubules. More specifically, SGLT2 is responsible for 80–90% of renal glucose reabsorption while SGLT1 is responsible for the remaining 10-20%. Under physiological conditions, less than one percent of glucose is excreted in urine. In the case of hyperglycemia, SGLTs become saturated and the renal threshold for urinary glucose excretion is increased. Kidneys respond to an elevated threshold for glycosuria by elevating glucose reabsorption and increasing maximum glucose reabsorptive capacity. Ertugliflozin is an inhibitor of SGLT2 that reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After administering single doses of 5 mg and 15 mg ertugliflozin under fasted conditions, the median T max was one hour. Plasma C max and AUC of ertugliflozin increase dose-proportionally. Following administration of a 15 mg dose, the C max was 268 ng/mL and the AUC was 1193 ng h/mL. The absolute oral bioavailability of ertugliflozin following administration of a 15 mg dose was approximately 100%, though it is reported to range from 70% to 90%. Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin C max by 29%. It prolongs T max by one hour but does not alter AUC compared to the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution following oral administration was 215.3 L. The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ertugliflozin is 93.6% bound to plasma proteins. Plasma protein binding is independent of ertugliflozin plasma concentrations and is not meaningfully altered in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ertugliflozin mainly undergoes O-glucuronidation mediated by UGT1A9 and UGT2B7 to form two pharmacologically inactive glucuronides. About 12% of the drug undergoes CYP-mediated oxidative metabolism. Several metabolites have been found in plasma, feces, and urine. In plasma, the unchanged form of ertugliflozin was found to be the major component of the administered dose. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following administration of an oral [ C]-ertugliflozin solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to form the parent compound. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half-life of ertugliflozin ranges from 11 to 17 hours. The mean elimination half-life in T2DM patients with normal renal function was estimated to be 16.6 hours based on the population pharmacokinetic analysis. •Clearance (Drug A): No clearance available •Clearance (Drug B): In one clinical involving healthy males, the apparent total plasma clearance rate after oral administration of ertugliflozin was 178.7 mL/min and the systemic total plasma clearance after intravenous administration was 187.2 ml/min. In another study, the mean systemic plasma clearance following an intravenous 100 µg dose was 11.2 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 500 mg/kg in rats. There are limited clinical experiences of ertugliflozin overdose. It is recommended to initiate supportive measures in the event of drug overdosage. Removal of ertugliflozin by hemodialysis has not been studied. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Segluromet, Steglatro, Steglujan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ertugliflozin is an SGLT2 inhibitor used to treat type 2 diabetes mellitus alone or in combination with other antidiabetic drugs.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Ertugliflozin interact? Information: •Drug A: Buserelin •Drug B: Ertugliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Ertugliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ertugliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus (T2DM). It is also available in combination with either metformin or sitagliptin. Ertugliflozin is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ertugliflozin causes a dose-dependent increase in urinary glucose excretion and an increase in urinary volume in patients with T2DM. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Kidneys play an integral role in glucose homeostasis. After being filtered into urine within the nephron, most of the plasma glucose is reabsorbed through two types of sodium-dependent glucose cotransporters (SGLTs), SGLT1 and SGLT2, expressed in proximal renal tubules. More specifically, SGLT2 is responsible for 80–90% of renal glucose reabsorption while SGLT1 is responsible for the remaining 10-20%. Under physiological conditions, less than one percent of glucose is excreted in urine. In the case of hyperglycemia, SGLTs become saturated and the renal threshold for urinary glucose excretion is increased. Kidneys respond to an elevated threshold for glycosuria by elevating glucose reabsorption and increasing maximum glucose reabsorptive capacity. Ertugliflozin is an inhibitor of SGLT2 that reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After administering single doses of 5 mg and 15 mg ertugliflozin under fasted conditions, the median T max was one hour. Plasma C max and AUC of ertugliflozin increase dose-proportionally. Following administration of a 15 mg dose, the C max was 268 ng/mL and the AUC was 1193 ng h/mL. The absolute oral bioavailability of ertugliflozin following administration of a 15 mg dose was approximately 100%, though it is reported to range from 70% to 90%. Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin C max by 29%. It prolongs T max by one hour but does not alter AUC compared to the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution following oral administration was 215.3 L. The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ertugliflozin is 93.6% bound to plasma proteins. Plasma protein binding is independent of ertugliflozin plasma concentrations and is not meaningfully altered in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ertugliflozin mainly undergoes O-glucuronidation mediated by UGT1A9 and UGT2B7 to form two pharmacologically inactive glucuronides. About 12% of the drug undergoes CYP-mediated oxidative metabolism. Several metabolites have been found in plasma, feces, and urine. In plasma, the unchanged form of ertugliflozin was found to be the major component of the administered dose. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following administration of an oral [ C]-ertugliflozin solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to form the parent compound. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half-life of ertugliflozin ranges from 11 to 17 hours. The mean elimination half-life in T2DM patients with normal renal function was estimated to be 16.6 hours based on the population pharmacokinetic analysis. •Clearance (Drug A): No clearance available •Clearance (Drug B): In one clinical involving healthy males, the apparent total plasma clearance rate after oral administration of ertugliflozin was 178.7 mL/min and the systemic total plasma clearance after intravenous administration was 187.2 ml/min. In another study, the mean systemic plasma clearance following an intravenous 100 µg dose was 11.2 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 500 mg/kg in rats. There are limited clinical experiences of ertugliflozin overdose. It is recommended to initiate supportive measures in the event of drug overdosage. Removal of ertugliflozin by hemodialysis has not been studied. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Segluromet, Steglatro, Steglujan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ertugliflozin is an SGLT2 inhibitor used to treat type 2 diabetes mellitus alone or in combination with other antidiabetic drugs. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Erythromycin interact?

•Drug A: Buserelin •Drug B: Erythromycin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Erythromycin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Erythromycin is indicated in the treatment of infections caused by susceptible strains of various bacteria. The indications for erythromycin have been summarized by body system below: Respiratory infections Mild to moderate upper respiratory tract infections caused by Streptococcus pyogenes, Streptococcus pneumoniae, or Haemophilus influenzae (when used concomitantly with appropriate doses of sulfonamides) can be treated with erythromycin. Mild to moderate lower-respiratory tract infections due to susceptible strains of Streptococcus pneumoniae or Streptococcus pyogenes may also be treated. Erythromycin treats listeriosis caused by Listeria monocytogenes may also be treated with erythromycin. Erythromycin is indicated to treat pertussis (whooping cough) caused by Bordetella pertussis. It is effective in eliminating the causative organism from the nasopharynx of infected individuals, rendering them noninfectious. Clinical studies suggest that erythromycin may aid in the prevention of pertussis infection for individuals who have been exposed to the bacteria. Respiratory tract infections due to Mycoplasma pneumoniae may also be treated with erythromycin. Despite the fact that no controlled clinical efficacy studies have been conducted to this date, in vitro and certain preliminary clinical study results indicate that erythromycin may be an effective treatment in Legionnaires’ Disease. Finally, erythromycin is indicated to treat diphtheria and other infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent carrier status and to eradicate the organism in existing carriers. In addition to the prevention of diphtheria, erythromycin can be used to prevent rheumatic fever in penicillin intolerant patients. Skin infections Mild to moderate skin or skin structure infections caused by Streptococcus pyogenes or Staphylococcus aureus may be treated with erythromycin, however, resistant staphylococcal organisms may emerge. Erythromycin can also be used to treat erythrasma, an infectious condition caused by Corynebacterium minutissimum. Gastrointestinal infections Intestinal amebiasis caused by Entamoeba histolytica can be treated with oral erythromycin. Extraenteric amebiasis warrants treatment with other antimicrobial drugs. Genital infections/STIs Erythromycin can be used as an alternative drug in treating acute pelvic inflammatory disease caused by N. gonorrheae in female patients who have demonstrated hypersensitivity or intolerance to penicillin. Syphilis, caused by Treponema pallidum, can be treated with erythromycin. It serves as an alternative treatment for primary syphilis in patients who have demonstrated penicillin hypersensitivity. Erythromycin can also be used in the primary stage of primary syphilis. Another approved indication of erythromycin is to treat chlamydial infections that cause conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections occurring in pregnancy. It is indicated as an alternative option to tetracyclines for the treatment of uncomplicated rectal, urethral and endocervical infections in adults caused by Chlamydia trachomatis. Erythromycin can be used in nongonococcal urethritis can be used when tetracyclines cannot be administered. Finally, erythromycin is indicated to treat nongonococcal urethritis due to Ureaplasma urealyticum. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Macrolides, such as erythromycin, stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Erythromycin does not exert effects on nucleic acid synthesis. This drug has been shown to be active against most strains of the following microorganisms, effectively treating both in vitro and clinical infections. Despite this, it is important to perform bacterial susceptibility testing before administering this antibiotic, as resistance is a common issue that may affect treatment. A note on antimicrobial resistance, pseudomembranous colitis, and hepatotoxicity Many strains of Haemophilus influenzae are resistant to erythromycin alone but are found to be susceptible to erythromycin and sulfonamides used in combination. It is important to note that Staphylococci that are resistant to erythromycin may emerge during erythromycin and/or sulfonamide therapy. Pseudomembranous colitis has been reported with most antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, the physician should consider this diagnosis in patients with diarrhea after the administration of antibacterial agents. Erythromycin can cause hepatic dysfunction, cholestatic jaundice, and abnormal liver transaminases, particularly when erythromycin estolate is administered. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Erythromycin acts by inhibition of protein synthesis by binding to the 23S ribosomal RNA molecule in the 50S subunit of ribosomes in susceptible bacterial organisms. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit. This results in the control of various bacterial infections. The strong affinity of macrolides, including erythromycin, for bacterial ribosomes, supports their broad‐spectrum antibacterial activities. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Orally administered erythromycin is readily absorbed. Food intake does not appear to exert effects on serum concentrations of erythromycin. Some interindividual variation exists in terms of erythromycin absorption, which may impact absorption to varying degrees. The Cmax of erythromycin is 1.8 mcg/L and the Tmax is 1.2 hours. The serum AUC of erythromycin after the administration of a 500mg oral dose was 7.3±3.9 mg.h/l in one pharmacokinetic study. Erythromycin is well known for a bioavailability that is variable (18-45%) after oral administration and its susceptibility to broken down under acidic conditions. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Erythromycin is found in most body fluids and accumulates in leucocytes and inflammatory liquid. Spinal fluid concentrations of erythromycin are low, however, the diffusion of erythromycin through the blood-brain barrier increases in meningitis, likely due to the presence of inflamed tissues which are easily penetrated. Erythromycin crosses the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): Erythromycin demonstrates 93% serum protein binding in the erythromycin propionate form. Another resource indicates that erythromycin protein binding ranges from 80 to 90%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic first-pass metabolism contributes significantly to erythromycin metabolism after an oral dose. Erythromycin is partially metabolized by CYP3A4 enzyme to N-desmethylerythromycin. Erythromycin is also hydrolyzed to anhydro forms (anhydroerythromycin [AHE] and other metabolites), and this process is promoted by acidic conditions. AHE is inactive against microbes but inhibits hepatic drug oxidation and is therefore considered to be an important contributor to erythromycin drug-drug interactions. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In patients with normal liver function, erythromycin concentrates in the liver and is then excreted in the bile. Under 5% of the orally administered dose of erythromycin is found excreted in the urine. A high percentage of absorbed erythromycin is not accounted for, but is likely metabolized. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of oral erythromycin was 3.5 hours according to one study and ranged between 2.4-3.1 hours in another study. Repetitive dosing of erythromycin leads to increased elimination half-life. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of erythromycin in healthy subjects was 0.53 ± 0.13 l/h/kg after a 125mg intravenous dose. In a clinical study of healthy patients and patients with liver cirrhosis, clearance of erythromycin was significantly reduced in those with severe liver cirrhosis. The clearance in cirrhotic patients was 42.2 ± 10.1 l h–1 versus 113.2 ± 44.2 l h-1 in healthy patients. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50 The oral LD50 of erythromycin in rats is 9272 mg/kg. Overdose information Symptoms of overdose may include diarrhea, nausea, stomach cramps, and vomiting. Erythromycin should immediately be discontinued in cases of overdose. Rapid elimination of unabsorbed drug should be attempted. Supportive measures should be initiated. Erythromycin is not adequately removed by peritoneal dialysis or hemodialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aktipak, Apo-Erythro-S, Benzamycin, E.E.S., Ery, Ery-tab, Erygel, Eryped, Erythro, Erythrocin, Erythrocin Stearate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Abomacetin Eritromicina Erythromycin Erythromycin A Erythromycin C érythromycine Erythromycinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Erythromycin is a macrolide antibiotic used to treat and prevent a variety of bacterial infections.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Erythromycin interact? Information: •Drug A: Buserelin •Drug B: Erythromycin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Erythromycin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Erythromycin is indicated in the treatment of infections caused by susceptible strains of various bacteria. The indications for erythromycin have been summarized by body system below: Respiratory infections Mild to moderate upper respiratory tract infections caused by Streptococcus pyogenes, Streptococcus pneumoniae, or Haemophilus influenzae (when used concomitantly with appropriate doses of sulfonamides) can be treated with erythromycin. Mild to moderate lower-respiratory tract infections due to susceptible strains of Streptococcus pneumoniae or Streptococcus pyogenes may also be treated. Erythromycin treats listeriosis caused by Listeria monocytogenes may also be treated with erythromycin. Erythromycin is indicated to treat pertussis (whooping cough) caused by Bordetella pertussis. It is effective in eliminating the causative organism from the nasopharynx of infected individuals, rendering them noninfectious. Clinical studies suggest that erythromycin may aid in the prevention of pertussis infection for individuals who have been exposed to the bacteria. Respiratory tract infections due to Mycoplasma pneumoniae may also be treated with erythromycin. Despite the fact that no controlled clinical efficacy studies have been conducted to this date, in vitro and certain preliminary clinical study results indicate that erythromycin may be an effective treatment in Legionnaires’ Disease. Finally, erythromycin is indicated to treat diphtheria and other infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent carrier status and to eradicate the organism in existing carriers. In addition to the prevention of diphtheria, erythromycin can be used to prevent rheumatic fever in penicillin intolerant patients. Skin infections Mild to moderate skin or skin structure infections caused by Streptococcus pyogenes or Staphylococcus aureus may be treated with erythromycin, however, resistant staphylococcal organisms may emerge. Erythromycin can also be used to treat erythrasma, an infectious condition caused by Corynebacterium minutissimum. Gastrointestinal infections Intestinal amebiasis caused by Entamoeba histolytica can be treated with oral erythromycin. Extraenteric amebiasis warrants treatment with other antimicrobial drugs. Genital infections/STIs Erythromycin can be used as an alternative drug in treating acute pelvic inflammatory disease caused by N. gonorrheae in female patients who have demonstrated hypersensitivity or intolerance to penicillin. Syphilis, caused by Treponema pallidum, can be treated with erythromycin. It serves as an alternative treatment for primary syphilis in patients who have demonstrated penicillin hypersensitivity. Erythromycin can also be used in the primary stage of primary syphilis. Another approved indication of erythromycin is to treat chlamydial infections that cause conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections occurring in pregnancy. It is indicated as an alternative option to tetracyclines for the treatment of uncomplicated rectal, urethral and endocervical infections in adults caused by Chlamydia trachomatis. Erythromycin can be used in nongonococcal urethritis can be used when tetracyclines cannot be administered. Finally, erythromycin is indicated to treat nongonococcal urethritis due to Ureaplasma urealyticum. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Macrolides, such as erythromycin, stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Erythromycin does not exert effects on nucleic acid synthesis. This drug has been shown to be active against most strains of the following microorganisms, effectively treating both in vitro and clinical infections. Despite this, it is important to perform bacterial susceptibility testing before administering this antibiotic, as resistance is a common issue that may affect treatment. A note on antimicrobial resistance, pseudomembranous colitis, and hepatotoxicity Many strains of Haemophilus influenzae are resistant to erythromycin alone but are found to be susceptible to erythromycin and sulfonamides used in combination. It is important to note that Staphylococci that are resistant to erythromycin may emerge during erythromycin and/or sulfonamide therapy. Pseudomembranous colitis has been reported with most antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, the physician should consider this diagnosis in patients with diarrhea after the administration of antibacterial agents. Erythromycin can cause hepatic dysfunction, cholestatic jaundice, and abnormal liver transaminases, particularly when erythromycin estolate is administered. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Erythromycin acts by inhibition of protein synthesis by binding to the 23S ribosomal RNA molecule in the 50S subunit of ribosomes in susceptible bacterial organisms. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit. This results in the control of various bacterial infections. The strong affinity of macrolides, including erythromycin, for bacterial ribosomes, supports their broad‐spectrum antibacterial activities. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Orally administered erythromycin is readily absorbed. Food intake does not appear to exert effects on serum concentrations of erythromycin. Some interindividual variation exists in terms of erythromycin absorption, which may impact absorption to varying degrees. The Cmax of erythromycin is 1.8 mcg/L and the Tmax is 1.2 hours. The serum AUC of erythromycin after the administration of a 500mg oral dose was 7.3±3.9 mg.h/l in one pharmacokinetic study. Erythromycin is well known for a bioavailability that is variable (18-45%) after oral administration and its susceptibility to broken down under acidic conditions. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Erythromycin is found in most body fluids and accumulates in leucocytes and inflammatory liquid. Spinal fluid concentrations of erythromycin are low, however, the diffusion of erythromycin through the blood-brain barrier increases in meningitis, likely due to the presence of inflamed tissues which are easily penetrated. Erythromycin crosses the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): Erythromycin demonstrates 93% serum protein binding in the erythromycin propionate form. Another resource indicates that erythromycin protein binding ranges from 80 to 90%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic first-pass metabolism contributes significantly to erythromycin metabolism after an oral dose. Erythromycin is partially metabolized by CYP3A4 enzyme to N-desmethylerythromycin. Erythromycin is also hydrolyzed to anhydro forms (anhydroerythromycin [AHE] and other metabolites), and this process is promoted by acidic conditions. AHE is inactive against microbes but inhibits hepatic drug oxidation and is therefore considered to be an important contributor to erythromycin drug-drug interactions. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In patients with normal liver function, erythromycin concentrates in the liver and is then excreted in the bile. Under 5% of the orally administered dose of erythromycin is found excreted in the urine. A high percentage of absorbed erythromycin is not accounted for, but is likely metabolized. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of oral erythromycin was 3.5 hours according to one study and ranged between 2.4-3.1 hours in another study. Repetitive dosing of erythromycin leads to increased elimination half-life. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of erythromycin in healthy subjects was 0.53 ± 0.13 l/h/kg after a 125mg intravenous dose. In a clinical study of healthy patients and patients with liver cirrhosis, clearance of erythromycin was significantly reduced in those with severe liver cirrhosis. The clearance in cirrhotic patients was 42.2 ± 10.1 l h–1 versus 113.2 ± 44.2 l h-1 in healthy patients. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50 The oral LD50 of erythromycin in rats is 9272 mg/kg. Overdose information Symptoms of overdose may include diarrhea, nausea, stomach cramps, and vomiting. Erythromycin should immediately be discontinued in cases of overdose. Rapid elimination of unabsorbed drug should be attempted. Supportive measures should be initiated. Erythromycin is not adequately removed by peritoneal dialysis or hemodialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aktipak, Apo-Erythro-S, Benzamycin, E.E.S., Ery, Ery-tab, Erygel, Eryped, Erythro, Erythrocin, Erythrocin Stearate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Abomacetin Eritromicina Erythromycin Erythromycin A Erythromycin C érythromycine Erythromycinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Erythromycin is a macrolide antibiotic used to treat and prevent a variety of bacterial infections. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Erythropoietin interact?

•Drug A: Buserelin •Drug B: Erythropoietin •Severity: MODERATE •Description: The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Buserelin. •Extended Description: Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated in adult and paediatric patients for the: treatment of anemia due to Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis. treatment of anemia due to zidovudine in patients with HIV-infection. treatment of anemia due to the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Erythropoietin and epoetin alfa are involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass. It is reported to increase the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. Depending on the dose administered, the rate of hemoglobin increase may vary. In patients receiving hemodialysis, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly. Epoetin alfa serves to restore erythropoietin deficiency in pathological and other clinical conditions where normal production of erythropoietin is impaired or compromised. In anemic patients with chronic renal failure (CRF), administration with epoetin alfa stimulated erythropoiesis by increasing the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. Epoetin alfa was shown to be effective in increasing hematocrit in zidovudine-treated HIV-infected patients and anemic cancer patients undergoing chemotherapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Erythropoietin or exogenous epoetin alfa binds to the erythropoietin receptor (EPO-R) and activates intracellular signal transduction pathways. The affinity (Kd) of EPO for its receptor on human cells is ∼100 to 200 pM. Upon binding to EPO-R on the surface of erythroid progenitor cells, a conformational change is induced which brings EPO-R-associated Janus family tyrosine protein kinase 2 (JAK2) molecules into close proximity. JAK2 molecules are subsequently activated via phosphorylation, then phosphorylate tyrosine residues in the cytoplasmic domain of the EPO-R that serve as docking sites for Src homology 2-domain-containing intracellular signaling proteins. The signalling proteins include STAT5 that once phosphorylated by JAK2, dissociates from the EPO-R, dimerizes, and translocates to the nucleus where they serve as transcription factors to activate target genes involved in cell division or differentiation, including the apoptosis inhibitor Bcl-x. The inhibition of apoptosis by the EPO-activated JAK2/STAT5/Bcl-x pathway is critical in erythroid differentiation. Via JAK2-mediated tyrosine phosphorylation, erythropoietin and epoetin alfa also activates other intracellular proteins involved in erythroid cell proliferation and survival, such as Shc, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The time to reach peak concentration is slower via the subcutaneous route than the intravenous route which ranges from 20 to 25 hours, and the peak is always well below the peak achieved using the intravenous route (5–10% of those seen with IV administration). The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40%. Adult and paediatric patients with CRF: Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours. Cancer patients receiving cyclic chemotherapy: The average time to reach peak plasma concentration was approximately 13.3 ± 12.4 hours after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The Cmax is expected be 3- to 7- fold higher and the Tmax is expected to be 2- to 3-fold longer in patients receiving a 40,000 Units SC weekly dosing regimen. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In healthy volunteers, the volume of distribution of intravenous epoetin alfa was generally similar to the plasma volume (range of 40–63.80 mL/kg), indicating limited extravascular distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): No information of serum protein binding available. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Binding of erythropoietin and epoetin alfa to EPO-R leads to cellular internalization, which involves the degradation of the ligand. Erythropoietin and epoetin alfa may also be degraded by the reticuloendothelial scavenging pathway or lymphatic system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Erythropoietin and epoetin alfa are cleared via uptake and degradation via the EPO-R-expressing cells, and may also involve other cellular pathways in the interstitium, probably via cells in the reticuloendothelial scavenging pathway or lymphatic system. Only a small amount of unchanged epoetin alfa is found in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Healthy volunteers: The half life is approximately 4 hours in healthy volunteers receiving an intravenous injection. A half-life of approximately 6 hours has been reported in children. Adult and paediatric patients with CRF: The elimination half life following intravenous administration ranges from 4 to 13 hours, which is about 20% longer in CRF patients than that in healthy subjects. The half life is reported to be similar between adult patients receiving or not receiving dialysis. Cancer patients receiving cyclic chemotherapy: Following subcutaneous administration, the average half life is 40 hours with range of 16 to 67 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): * Healthy volunteers: * In male volunteers receiving intravenous epoetin alfa, the total body clearance was approximately 8.12 ± 1.00 mL/h/kg. Cancer patients receiving cyclic chemotherapy: The average clearance was approximately 20.2 ± 15.9 mL/h/kg after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The patients receiving a 40,000 Units SC weekly dosing regimen display a lower clearance (9.2 ± 4.7 mL/h/kg). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose from epoetin alfa include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including cardiovascular events. Patients with suspected or known overdose should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the overdose, reintroduction of epoetin alfa therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the dose in accordance with the recommendations described in the drug label. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Abseamed, Epoetin Alfa Hexal, Epogen, Eporatio, Epprex, Eprex, Procrit, Retacrit, Silapo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Erythropoietin is a recombinant form of human erythropoietin used to increase differentiation of progenitor cells to red blood cells in the treatment of anemia.

Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. The severity of the interaction is moderate.

Question: Does Buserelin and Erythropoietin interact? Information: •Drug A: Buserelin •Drug B: Erythropoietin •Severity: MODERATE •Description: The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Buserelin. •Extended Description: Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated in adult and paediatric patients for the: treatment of anemia due to Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis. treatment of anemia due to zidovudine in patients with HIV-infection. treatment of anemia due to the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Erythropoietin and epoetin alfa are involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass. It is reported to increase the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. Depending on the dose administered, the rate of hemoglobin increase may vary. In patients receiving hemodialysis, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly. Epoetin alfa serves to restore erythropoietin deficiency in pathological and other clinical conditions where normal production of erythropoietin is impaired or compromised. In anemic patients with chronic renal failure (CRF), administration with epoetin alfa stimulated erythropoiesis by increasing the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. Epoetin alfa was shown to be effective in increasing hematocrit in zidovudine-treated HIV-infected patients and anemic cancer patients undergoing chemotherapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Erythropoietin or exogenous epoetin alfa binds to the erythropoietin receptor (EPO-R) and activates intracellular signal transduction pathways. The affinity (Kd) of EPO for its receptor on human cells is ∼100 to 200 pM. Upon binding to EPO-R on the surface of erythroid progenitor cells, a conformational change is induced which brings EPO-R-associated Janus family tyrosine protein kinase 2 (JAK2) molecules into close proximity. JAK2 molecules are subsequently activated via phosphorylation, then phosphorylate tyrosine residues in the cytoplasmic domain of the EPO-R that serve as docking sites for Src homology 2-domain-containing intracellular signaling proteins. The signalling proteins include STAT5 that once phosphorylated by JAK2, dissociates from the EPO-R, dimerizes, and translocates to the nucleus where they serve as transcription factors to activate target genes involved in cell division or differentiation, including the apoptosis inhibitor Bcl-x. The inhibition of apoptosis by the EPO-activated JAK2/STAT5/Bcl-x pathway is critical in erythroid differentiation. Via JAK2-mediated tyrosine phosphorylation, erythropoietin and epoetin alfa also activates other intracellular proteins involved in erythroid cell proliferation and survival, such as Shc, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The time to reach peak concentration is slower via the subcutaneous route than the intravenous route which ranges from 20 to 25 hours, and the peak is always well below the peak achieved using the intravenous route (5–10% of those seen with IV administration). The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40%. Adult and paediatric patients with CRF: Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours. Cancer patients receiving cyclic chemotherapy: The average time to reach peak plasma concentration was approximately 13.3 ± 12.4 hours after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The Cmax is expected be 3- to 7- fold higher and the Tmax is expected to be 2- to 3-fold longer in patients receiving a 40,000 Units SC weekly dosing regimen. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In healthy volunteers, the volume of distribution of intravenous epoetin alfa was generally similar to the plasma volume (range of 40–63.80 mL/kg), indicating limited extravascular distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): No information of serum protein binding available. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Binding of erythropoietin and epoetin alfa to EPO-R leads to cellular internalization, which involves the degradation of the ligand. Erythropoietin and epoetin alfa may also be degraded by the reticuloendothelial scavenging pathway or lymphatic system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Erythropoietin and epoetin alfa are cleared via uptake and degradation via the EPO-R-expressing cells, and may also involve other cellular pathways in the interstitium, probably via cells in the reticuloendothelial scavenging pathway or lymphatic system. Only a small amount of unchanged epoetin alfa is found in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Healthy volunteers: The half life is approximately 4 hours in healthy volunteers receiving an intravenous injection. A half-life of approximately 6 hours has been reported in children. Adult and paediatric patients with CRF: The elimination half life following intravenous administration ranges from 4 to 13 hours, which is about 20% longer in CRF patients than that in healthy subjects. The half life is reported to be similar between adult patients receiving or not receiving dialysis. Cancer patients receiving cyclic chemotherapy: Following subcutaneous administration, the average half life is 40 hours with range of 16 to 67 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): * Healthy volunteers: * In male volunteers receiving intravenous epoetin alfa, the total body clearance was approximately 8.12 ± 1.00 mL/h/kg. Cancer patients receiving cyclic chemotherapy: The average clearance was approximately 20.2 ± 15.9 mL/h/kg after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The patients receiving a 40,000 Units SC weekly dosing regimen display a lower clearance (9.2 ± 4.7 mL/h/kg). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose from epoetin alfa include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including cardiovascular events. Patients with suspected or known overdose should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the overdose, reintroduction of epoetin alfa therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the dose in accordance with the recommendations described in the drug label. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Abseamed, Epoetin Alfa Hexal, Epogen, Eporatio, Epprex, Eprex, Procrit, Retacrit, Silapo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Erythropoietin is a recombinant form of human erythropoietin used to increase differentiation of progenitor cells to red blood cells in the treatment of anemia. Output: Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. The severity of the interaction is moderate.

Does Buserelin and Escitalopram interact?

•Drug A: Buserelin •Drug B: Escitalopram •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Escitalopram. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Escitalopram is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years old and older and for the acute treatment of generalized anxiety disorder (GAD) in adults and pediatric patients 7 years old and older. It is additionally indicated for symptomatic relief of obsessive-compulsive disorder (OCD) in Canada. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Escitalopram belongs to a class of medications called selective serotonin re-uptake inhibitors (SSRIs). These agents cause an increase in serotonin levels in neuronal synapses by preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic neurons. As compared to other SSRIs, it appears to have a relatively quick onset of effect due to its potency. SSRIs as a class have been associated with abnormal bleeding, particularly in patients receiving concomitant therapy with other medications affecting hemostasis, and with the development of serotonin syndrome. Use escitalopram with caution in patients with a higher-than-baseline risk of bleeding and in patients receiving concomitant therapy with other serotonergic drugs. Escitalopram may also cause a discontinuation syndrome with abrupt removal of the drug, and should be slowly tapered if discontinuation of therapy is warranted. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with paroxetine, is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT 1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action. Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. T max occurs after about 4-5 hours. C max and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a C max of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both C max and 24h AUC, comparatively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Escitalopram exhibits relatively low protein binding at approximately 55-56%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose may include CNS effects (dizziness, convulsions, coma, somnolence), gastrointestinal distress (nausea, vomiting), and/or cardiac abnormalities (hypotension, tachycardia, ECG changes). There is no specific antidote for escitalopram overdose. Management of overdose should focus on monitoring for cardiac abnormalities and changes to vital signs as well as treatment with supportive measures as indicated. As escitalopram is highly distributed into tissue following oral administration, forced diuresis, dialysis, and other methods of extracting drug from plasma are unlikely to be beneficial. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cipralex, Lexapro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Citalopram Escitalopram Escitalopramum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Escitalopram is a selective serotonin re-uptake inhibitor used in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and other select psychiatric disorders such as obsessive-compulsive disorder (OCD).

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Escitalopram interact? Information: •Drug A: Buserelin •Drug B: Escitalopram •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Escitalopram. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Escitalopram is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years old and older and for the acute treatment of generalized anxiety disorder (GAD) in adults and pediatric patients 7 years old and older. It is additionally indicated for symptomatic relief of obsessive-compulsive disorder (OCD) in Canada. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Escitalopram belongs to a class of medications called selective serotonin re-uptake inhibitors (SSRIs). These agents cause an increase in serotonin levels in neuronal synapses by preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic neurons. As compared to other SSRIs, it appears to have a relatively quick onset of effect due to its potency. SSRIs as a class have been associated with abnormal bleeding, particularly in patients receiving concomitant therapy with other medications affecting hemostasis, and with the development of serotonin syndrome. Use escitalopram with caution in patients with a higher-than-baseline risk of bleeding and in patients receiving concomitant therapy with other serotonergic drugs. Escitalopram may also cause a discontinuation syndrome with abrupt removal of the drug, and should be slowly tapered if discontinuation of therapy is warranted. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with paroxetine, is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT 1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action. Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. T max occurs after about 4-5 hours. C max and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a C max of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both C max and 24h AUC, comparatively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Escitalopram exhibits relatively low protein binding at approximately 55-56%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose may include CNS effects (dizziness, convulsions, coma, somnolence), gastrointestinal distress (nausea, vomiting), and/or cardiac abnormalities (hypotension, tachycardia, ECG changes). There is no specific antidote for escitalopram overdose. Management of overdose should focus on monitoring for cardiac abnormalities and changes to vital signs as well as treatment with supportive measures as indicated. As escitalopram is highly distributed into tissue following oral administration, forced diuresis, dialysis, and other methods of extracting drug from plasma are unlikely to be beneficial. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cipralex, Lexapro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Citalopram Escitalopram Escitalopramum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Escitalopram is a selective serotonin re-uptake inhibitor used in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and other select psychiatric disorders such as obsessive-compulsive disorder (OCD). Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Esmolol interact?

•Drug A: Buserelin •Drug B: Esmolol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Esmolol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/mm) are obtained within five minutes. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 55% bound to human plasma protein, while the acid metabolite is 10% bound. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 20 L/kg/hr [Men] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Brevibloc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Esmolol •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Esmolol interact? Information: •Drug A: Buserelin •Drug B: Esmolol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Esmolol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/mm) are obtained within five minutes. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 55% bound to human plasma protein, while the acid metabolite is 10% bound. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 20 L/kg/hr [Men] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Brevibloc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Esmolol •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ethosuximide interact?

•Drug A: Buserelin •Drug B: Ethosuximide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ethosuximide is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of petit mal epilepsy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Used in the treatment of epilepsy. Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bioavailability following oral administration is 93%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic, via CYP3A4 and CYP2E1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 53 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zarontin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aethosuximide Atysmal Ethosuximid Ethosuximide éthosuximide Ethosuximidum Etosuximida Thilopemal •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ethosuximide is an anticonvulsant used to treat petit mal seizures.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ethosuximide interact? Information: •Drug A: Buserelin •Drug B: Ethosuximide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ethosuximide is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of petit mal epilepsy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Used in the treatment of epilepsy. Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bioavailability following oral administration is 93%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic, via CYP3A4 and CYP2E1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 53 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zarontin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aethosuximide Atysmal Ethosuximid Ethosuximide éthosuximide Ethosuximidum Etosuximida Thilopemal •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ethosuximide is an anticonvulsant used to treat petit mal seizures. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ethyl chloride interact?

•Drug A: Buserelin •Drug B: Ethyl chloride •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Ethyl chloride. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ethyl chloride is a local anesthetic.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Ethyl chloride interact? Information: •Drug A: Buserelin •Drug B: Ethyl chloride •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Ethyl chloride. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ethyl chloride is a local anesthetic. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Etrasimod interact?

•Drug A: Buserelin •Drug B: Etrasimod •Severity: MODERATE •Description: The risk or severity of QTc prolongation and torsade de pointes can be increased when Etrasimod is combined with Buserelin. •Extended Description: Etrasimod has been reported to cause a transient decrease in heart rate and AV conduction delays. This is likely due to the modulation of the S1P receptors that leads to the activation of the G-protein coupled inwardly rectifying potassium channels (GIRK) that regulate the pacemaker activity, thus resulting in a negative inotropic effect.[A261821] Therefore, the concomitant use of etrasimod and a QTc prolonging agent can increase the risk of QTc prolongation and Torsade de Pointes. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Etrasimod causes a reduction in peripheral blood lymphocyte count. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with etrasimod. Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing etrasimod 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks. Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of etrasimod on Day 1. At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation. Reductions in absolute FEV1 were also observed in subjects treated with etrasimod. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P 1,4,5 ). Etrasimod has minimal activity on S1P 3 (25-fold lower than C max at the recommended dose) and no activity on S1P 2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Etrasimod mean (SD) steady-state maximum plasma concentration (C max ) was 113 (27.5) ng/mL and the area under the time concentration curve at the dosing interval (AUC tau ) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod C max and AUC are approximately dose-proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose. The median (range) time to reach etrasimod C max (T max ) is approximately 4 hours (range 2 to 8 hours) after oral administration. No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of etrasimod with a high-fat meal (800 to 1000 calories). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent volume of distribution of etrasimod is 66 (24) L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Etrasimod plasma protein binding is 97.9%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 82% of the total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of the administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean plasma elimination half-life (t 1/2 ) of etrasimod is approximately 30 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent steady-state oral clearance of etrasimod is approximately 1 L/h after oral administration. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Based on findings from animal studies, etrasimod may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with etrasimod are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the maximum recommended human dose (MRHD) of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17. No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD). In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (7 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (7 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD). In a pre-and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD). Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD). Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at MRHD). Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays. Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Velsipity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Etrasimod is an S1P receptors modulator used to treat moderate to severely active ulcerative colitis in adults

Etrasimod has been reported to cause a transient decrease in heart rate and AV conduction delays. This is likely due to the modulation of the S1P receptors that leads to the activation of the G-protein coupled inwardly rectifying potassium channels (GIRK) that regulate the pacemaker activity, thus resulting in a negative inotropic effect.[A261821] Therefore, the concomitant use of etrasimod and a QTc prolonging agent can increase the risk of QTc prolongation and Torsade de Pointes. The severity of the interaction is moderate.

Question: Does Buserelin and Etrasimod interact? Information: •Drug A: Buserelin •Drug B: Etrasimod •Severity: MODERATE •Description: The risk or severity of QTc prolongation and torsade de pointes can be increased when Etrasimod is combined with Buserelin. •Extended Description: Etrasimod has been reported to cause a transient decrease in heart rate and AV conduction delays. This is likely due to the modulation of the S1P receptors that leads to the activation of the G-protein coupled inwardly rectifying potassium channels (GIRK) that regulate the pacemaker activity, thus resulting in a negative inotropic effect.[A261821] Therefore, the concomitant use of etrasimod and a QTc prolonging agent can increase the risk of QTc prolongation and Torsade de Pointes. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Etrasimod causes a reduction in peripheral blood lymphocyte count. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with etrasimod. Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing etrasimod 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks. Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of etrasimod on Day 1. At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation. Reductions in absolute FEV1 were also observed in subjects treated with etrasimod. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P 1,4,5 ). Etrasimod has minimal activity on S1P 3 (25-fold lower than C max at the recommended dose) and no activity on S1P 2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Etrasimod mean (SD) steady-state maximum plasma concentration (C max ) was 113 (27.5) ng/mL and the area under the time concentration curve at the dosing interval (AUC tau ) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod C max and AUC are approximately dose-proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose. The median (range) time to reach etrasimod C max (T max ) is approximately 4 hours (range 2 to 8 hours) after oral administration. No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of etrasimod with a high-fat meal (800 to 1000 calories). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent volume of distribution of etrasimod is 66 (24) L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Etrasimod plasma protein binding is 97.9%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 82% of the total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of the administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean plasma elimination half-life (t 1/2 ) of etrasimod is approximately 30 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent steady-state oral clearance of etrasimod is approximately 1 L/h after oral administration. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Based on findings from animal studies, etrasimod may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with etrasimod are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the maximum recommended human dose (MRHD) of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17. No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD). In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (7 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (7 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD). In a pre-and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD). Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD). Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at MRHD). Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays. Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Velsipity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Etrasimod is an S1P receptors modulator used to treat moderate to severely active ulcerative colitis in adults Output: Etrasimod has been reported to cause a transient decrease in heart rate and AV conduction delays. This is likely due to the modulation of the S1P receptors that leads to the activation of the G-protein coupled inwardly rectifying potassium channels (GIRK) that regulate the pacemaker activity, thus resulting in a negative inotropic effect.[A261821] Therefore, the concomitant use of etrasimod and a QTc prolonging agent can increase the risk of QTc prolongation and Torsade de Pointes. The severity of the interaction is moderate.

Does Buserelin and Exenatide interact?

•Drug A: Buserelin •Drug B: Exenatide •Severity: MODERATE •Description: The therapeutic efficacy of Exenatide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Exenatide is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. An extended-release formulation is available which is indicated in patients ≥10 years old, while the immediate-acting formulation is approved only for adult patients. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): When patients take exenatide the body's natural response to glucose is modulated. More insulin and less glucagon are released in response to glucose, though in cases of hypoglycemia a normal amount of glucagon is released. Exenatide also slows gastric emptying, leading to a slower and prolonged release of glucose into the systemic circulation. Together these effects prevent hyper and hypoglycemia. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Exenatide is a human glucacon-like peptide-1(GLP-1) receptor agonist. By activating this receptor, insulin secretion is increased and glucagon secretion is decreased in a glucose dependant manner. Exenatide also slows gastric emptying and decreases food intake. These effects work synergistically to improve glycemic control by reducing the likelihood of hyper and hypoglycemia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Exenatide reaches a peak plasma concentration in 2.1 hours. Because exenatide is administerd subcutaneously, the bioavailability is 1. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 28.3L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Protein binding of exenatide has not been determined. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Exenatide is filtered through the glomerulus before being degraded to smaller peptides and amino acids by dipeptidyl peptidase-4, metalloproteases, endopeptidase 24-11, amino proteases, and serine proteases. It is currently believed that the metalloproteases are responsible for most of the degradation of exenatide. Exenatide is metabolised to small peptides <3 amino acids in length by enzymes in the kidney. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Exenatide is mainly eliminated by glomerular filtration followed by proteolysis before finally being eliminated in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2.4 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 9.1 L/hour. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In animal studies, exenatide was associated with fetal deformities of ribs and vertebrae as well as slowed growth. In humans, uncontrolled hyperglycemia can be associated with an up to 25% risk of miscarriage. No human studies in pregnancy have been performed with exenatide and so exenatide should only be prescribed in pregnancy if the benefit to the mother and fetus outweigh the risks. In mice, exenatide is excreted in the milk at a concentration 2.5% of the plasma concentration though this data may not be applicable to humans. The effect of exenatide on breastfed infants is also unknown and so the risk and benefit of breastfeeding while taking exenatide must be weighed. There is no data for the use of exenatide in pediatric patients. Geriatric patients do not have different results for safety and efficacy of exenatide though caution should still be used in this group as they are at higher risk of renal impairment or other comorbidities that may affect the liklihood of adverse effects. No dosage adjustments are necessary for patients with creatinine clearance ≥50mL/min, though prescribing to patients with creatinine clearance 30-50mL/min should be done cautiously. Exenatide is not recommended for patients with creatinine clearance <30mL/min. Hepatic impairment is not expected to affect clearance of exenatide though no studies have been performed to confirm this. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bydureon, Byetta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Exenatide is a GLP-1 agonist used in the management of type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Exenatide interact? Information: •Drug A: Buserelin •Drug B: Exenatide •Severity: MODERATE •Description: The therapeutic efficacy of Exenatide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Exenatide is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. An extended-release formulation is available which is indicated in patients ≥10 years old, while the immediate-acting formulation is approved only for adult patients. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): When patients take exenatide the body's natural response to glucose is modulated. More insulin and less glucagon are released in response to glucose, though in cases of hypoglycemia a normal amount of glucagon is released. Exenatide also slows gastric emptying, leading to a slower and prolonged release of glucose into the systemic circulation. Together these effects prevent hyper and hypoglycemia. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Exenatide is a human glucacon-like peptide-1(GLP-1) receptor agonist. By activating this receptor, insulin secretion is increased and glucagon secretion is decreased in a glucose dependant manner. Exenatide also slows gastric emptying and decreases food intake. These effects work synergistically to improve glycemic control by reducing the likelihood of hyper and hypoglycemia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Exenatide reaches a peak plasma concentration in 2.1 hours. Because exenatide is administerd subcutaneously, the bioavailability is 1. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 28.3L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Protein binding of exenatide has not been determined. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Exenatide is filtered through the glomerulus before being degraded to smaller peptides and amino acids by dipeptidyl peptidase-4, metalloproteases, endopeptidase 24-11, amino proteases, and serine proteases. It is currently believed that the metalloproteases are responsible for most of the degradation of exenatide. Exenatide is metabolised to small peptides <3 amino acids in length by enzymes in the kidney. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Exenatide is mainly eliminated by glomerular filtration followed by proteolysis before finally being eliminated in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2.4 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 9.1 L/hour. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In animal studies, exenatide was associated with fetal deformities of ribs and vertebrae as well as slowed growth. In humans, uncontrolled hyperglycemia can be associated with an up to 25% risk of miscarriage. No human studies in pregnancy have been performed with exenatide and so exenatide should only be prescribed in pregnancy if the benefit to the mother and fetus outweigh the risks. In mice, exenatide is excreted in the milk at a concentration 2.5% of the plasma concentration though this data may not be applicable to humans. The effect of exenatide on breastfed infants is also unknown and so the risk and benefit of breastfeeding while taking exenatide must be weighed. There is no data for the use of exenatide in pediatric patients. Geriatric patients do not have different results for safety and efficacy of exenatide though caution should still be used in this group as they are at higher risk of renal impairment or other comorbidities that may affect the liklihood of adverse effects. No dosage adjustments are necessary for patients with creatinine clearance ≥50mL/min, though prescribing to patients with creatinine clearance 30-50mL/min should be done cautiously. Exenatide is not recommended for patients with creatinine clearance <30mL/min. Hepatic impairment is not expected to affect clearance of exenatide though no studies have been performed to confirm this. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bydureon, Byetta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Exenatide is a GLP-1 agonist used in the management of type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Famotidine interact?

•Drug A: Buserelin •Drug B: Famotidine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Famotidine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Famotidine is indicated in pediatric and adult patients (with the bodyweight of 40 kg and above) for the management of active duodenal ulcer (DU), active gastric ulcer, symptomatic non-erosive gastroesophageal reflux disease (GERD), and erosive esophagitis due to GERD, diagnosed by biopsy. It is also indicated in adult patients for the treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine neoplasias) and reduction of the risk of DU recurrence. The intravenous formulation of famotidine is available for some hospitalized patients with pathological hypersecretory conditions or intractable ulcers or as an alternative to the oral dosage form for short-term use in patients who are unable to take oral medication. Over-the-counter famotidine is used for the management and prevention of heartburn caused by gastroesophageal reflux in children and adults. Off-label uses of famotidine include the reduction of NSAIDs-associated gastrointestinal effects, treatment of refractory urticarial, prevention of stress ulcer in critically-ill patients, and symptomatic relief of gastritis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Famotidine decreases the production of gastric acid, suppresses acid concentration and pepsin content, and decreases the volume of gastric secretion. Famotidine inhibits both basal and nocturnal gastric acid secretion, as well as acid secretion stimulated by food, caffeine, insulin, and pentagastrin. Famotidine has a dose-dependent therapeutic action, with the highest dose having the most extended duration of action and the highest inhibitory effect on gastric acid secretion. Following oral administration, the onset of action is within one hour, and the peak effect is reached within 1-3 hours. The duration of effect is about 10-12 hours. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Histamine acts as a local hormone that stimulates the acid output by parietal cells via a paracrine mechanism. Neuroendocrine cells called enterochromaffin-like (ECL) cells lie close to the parietal cells and regulate the basal secretion of histamine. Histamine release is also promoted from stimulation by acetylcholine and gastrin, a peptide hormone. Gastrin (G) cells release gastrin, which works on CCK 2 receptors on ECL cells. This action promotes the release of histamine from ECL cells. Upon release, histamine acts on H 2 receptors expressed on the basolateral membrane of parietal cells, leading to increased intracellular cAMP levels and activated proton pumps on parietal cells. Proton pump releases more protons into the stomach, thereby increasing the secretion of acid. In conditions that are associated with acid hypersecretion such as ulcers, there is a loss of regulation of acid secretion. Famotidine works on H 2 receptors and blocks the actions of histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, the absorption of famotidine is dose-dependent and incomplete. The oral bioavailability ranges from 40-50%, and the Cmax is reached in 1-4 hours post-dosing. While the bioavailability can be slightly increased with the intake of food and decreased by antacids, there is no clinical significance. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady-state volume of distribution ranges from 1.0 to 1.3 L/kg. Famotidine is found in breast milk; however, it is found in breast milk at the lowest concentrations compared to other H 2 receptor antagonists. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of famotidine is about 15 to 22%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Famotidine undergoes minimal first-pass metabolism. About 25-30% of the drug is eliminated through hepatic metabolism. The only metabolite identified in humans is the S-oxide. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): About 65-70% of the total administered dose of famotidine undergoes renal elimination, and 30-35% of the dose is cleared by metabolism. Following intravenous administration, about 70% of the drug is eliminated in the urine as an unchanged drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life is about 2 to 4 hours. The half-life is expected to increase nonlinearly in patients with decreased renal function. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance is 250-450 mL/min, indicating some tubular excretion. Because the renal clearance rate exceeds the glomerular filtration rate, famotidine is thought to be mainly eliminated via both glomerular filtration and renal tubular secretion. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 4049 mg/kg in rats and 4686 mg/kg in mice. The subcutaneous LD 50 is 800 mg/kg in rats and mice. The intraperitoneal LD 50 is 800 mg/kg in rats and 778 mg/kg in mice. The intravenous LD 50 is 204 mg/kg in rats and 254 mg/kg in mice. The lowest published toxic dose (TDLo) in man following oral administration is 4 mg/kg/7D. Symptoms of overdose resemble the adverse events seen with the use of recommended doses, and they should be responded with supportive and symptomatic treatment. Any unabsorbed drug should be removed from the gastrointestinal tract, and the patient should be monitored accordingly. The use of hemodialysis to eliminate the drug from the systemic circulation is effective, but the experience of using hemodialysis in response to famotidine overdose is limited in clinical settings. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Duexis, Duo Fusion, Fluxid, Good Sense Acid Reducer, Pepcid, Pepcid Complete, Zantac Reformulated Aug 2022 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Famotidina Famotidine Famotidinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Famotidine is a histamine H2 receptor antagonist used to treat duodenal ulcers, benign gastric ulcers, GERD, and Zollinger-Ellison syndrome.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Famotidine interact? Information: •Drug A: Buserelin •Drug B: Famotidine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Famotidine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Famotidine is indicated in pediatric and adult patients (with the bodyweight of 40 kg and above) for the management of active duodenal ulcer (DU), active gastric ulcer, symptomatic non-erosive gastroesophageal reflux disease (GERD), and erosive esophagitis due to GERD, diagnosed by biopsy. It is also indicated in adult patients for the treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine neoplasias) and reduction of the risk of DU recurrence. The intravenous formulation of famotidine is available for some hospitalized patients with pathological hypersecretory conditions or intractable ulcers or as an alternative to the oral dosage form for short-term use in patients who are unable to take oral medication. Over-the-counter famotidine is used for the management and prevention of heartburn caused by gastroesophageal reflux in children and adults. Off-label uses of famotidine include the reduction of NSAIDs-associated gastrointestinal effects, treatment of refractory urticarial, prevention of stress ulcer in critically-ill patients, and symptomatic relief of gastritis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Famotidine decreases the production of gastric acid, suppresses acid concentration and pepsin content, and decreases the volume of gastric secretion. Famotidine inhibits both basal and nocturnal gastric acid secretion, as well as acid secretion stimulated by food, caffeine, insulin, and pentagastrin. Famotidine has a dose-dependent therapeutic action, with the highest dose having the most extended duration of action and the highest inhibitory effect on gastric acid secretion. Following oral administration, the onset of action is within one hour, and the peak effect is reached within 1-3 hours. The duration of effect is about 10-12 hours. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Histamine acts as a local hormone that stimulates the acid output by parietal cells via a paracrine mechanism. Neuroendocrine cells called enterochromaffin-like (ECL) cells lie close to the parietal cells and regulate the basal secretion of histamine. Histamine release is also promoted from stimulation by acetylcholine and gastrin, a peptide hormone. Gastrin (G) cells release gastrin, which works on CCK 2 receptors on ECL cells. This action promotes the release of histamine from ECL cells. Upon release, histamine acts on H 2 receptors expressed on the basolateral membrane of parietal cells, leading to increased intracellular cAMP levels and activated proton pumps on parietal cells. Proton pump releases more protons into the stomach, thereby increasing the secretion of acid. In conditions that are associated with acid hypersecretion such as ulcers, there is a loss of regulation of acid secretion. Famotidine works on H 2 receptors and blocks the actions of histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, the absorption of famotidine is dose-dependent and incomplete. The oral bioavailability ranges from 40-50%, and the Cmax is reached in 1-4 hours post-dosing. While the bioavailability can be slightly increased with the intake of food and decreased by antacids, there is no clinical significance. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady-state volume of distribution ranges from 1.0 to 1.3 L/kg. Famotidine is found in breast milk; however, it is found in breast milk at the lowest concentrations compared to other H 2 receptor antagonists. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of famotidine is about 15 to 22%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Famotidine undergoes minimal first-pass metabolism. About 25-30% of the drug is eliminated through hepatic metabolism. The only metabolite identified in humans is the S-oxide. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): About 65-70% of the total administered dose of famotidine undergoes renal elimination, and 30-35% of the dose is cleared by metabolism. Following intravenous administration, about 70% of the drug is eliminated in the urine as an unchanged drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life is about 2 to 4 hours. The half-life is expected to increase nonlinearly in patients with decreased renal function. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance is 250-450 mL/min, indicating some tubular excretion. Because the renal clearance rate exceeds the glomerular filtration rate, famotidine is thought to be mainly eliminated via both glomerular filtration and renal tubular secretion. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 4049 mg/kg in rats and 4686 mg/kg in mice. The subcutaneous LD 50 is 800 mg/kg in rats and mice. The intraperitoneal LD 50 is 800 mg/kg in rats and 778 mg/kg in mice. The intravenous LD 50 is 204 mg/kg in rats and 254 mg/kg in mice. The lowest published toxic dose (TDLo) in man following oral administration is 4 mg/kg/7D. Symptoms of overdose resemble the adverse events seen with the use of recommended doses, and they should be responded with supportive and symptomatic treatment. Any unabsorbed drug should be removed from the gastrointestinal tract, and the patient should be monitored accordingly. The use of hemodialysis to eliminate the drug from the systemic circulation is effective, but the experience of using hemodialysis in response to famotidine overdose is limited in clinical settings. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Duexis, Duo Fusion, Fluxid, Good Sense Acid Reducer, Pepcid, Pepcid Complete, Zantac Reformulated Aug 2022 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Famotidina Famotidine Famotidinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Famotidine is a histamine H2 receptor antagonist used to treat duodenal ulcers, benign gastric ulcers, GERD, and Zollinger-Ellison syndrome. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Felbamate interact?

•Drug A: Buserelin •Drug B: Felbamate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Felbamate is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Felbamate is an antiepileptic indicated as monotherapy or as an adjunct to other anticonvulsants for the treatment of partial seizures resulting from epilepsy. Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. In vitro receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): >90% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 756±82 mL/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 20-36% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 20-23 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 26 +/- 3 mL/hr/kg [single 1200 mg dose] 30 +/- 8 mL/hr/kg [multiple daily doses of 3600 mg] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =5000 mg/kg (Orally in rats) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Felbatol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felbamate Felbamato Felbamatum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Felbamate is an anticonvulsant used to treat severe epilepsy.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Felbamate interact? Information: •Drug A: Buserelin •Drug B: Felbamate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Felbamate is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Felbamate is an antiepileptic indicated as monotherapy or as an adjunct to other anticonvulsants for the treatment of partial seizures resulting from epilepsy. Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. In vitro receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): >90% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 756±82 mL/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 20-36% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 20-23 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 26 +/- 3 mL/hr/kg [single 1200 mg dose] 30 +/- 8 mL/hr/kg [multiple daily doses of 3600 mg] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =5000 mg/kg (Orally in rats) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Felbatol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felbamate Felbamato Felbamatum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Felbamate is an anticonvulsant used to treat severe epilepsy. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Felodipine interact?

•Drug A: Buserelin •Drug B: Felodipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Felodipine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of mild to moderate essential hypertension. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 10 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 99%, primarily to the albumin fraction. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.8 L/min [Young healthy subjects] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Plendil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felodipina Felodipine Felodipino Felodipinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Felodipine is a calcium channel blocker used to treat hypertension.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Felodipine interact? Information: •Drug A: Buserelin •Drug B: Felodipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Felodipine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of mild to moderate essential hypertension. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 10 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 99%, primarily to the albumin fraction. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.8 L/min [Young healthy subjects] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Plendil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felodipina Felodipine Felodipino Felodipinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Felodipine is a calcium channel blocker used to treat hypertension. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Fexinidazole interact?

•Drug A: Buserelin •Drug B: Fexinidazole •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Buserelin is combined with Fexinidazole. •Extended Description: Coadministration of fexinidazole with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fexinidazole is a nitroimidazole indicated for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in patients 6 years of age and older weighing at least 20 kg. Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL), fexinidazole should only be used in these patients if there are no other available treatment options. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fexinidazole is a 2-substituted 5-nitroimidazole that is likely activated by parasitic nitroreductases to highly reactive species, leading to DNA and protein damage and eventual parasite death. The dosing schedule is designed to ensure a high enough concentration of fexinidazole and its reactive metabolites for at least 48 hours, which from in vitro studies was shown to be the minimum exposure time that was effectively trypanocidal. Although fexinidazole is effective in late-stage T. brucei gambiense HAT, it is less effective than NECT therapy in patients with severe (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL at baseline) disease. It should only be used in these patients if there are no other available treatment options. Fexinidazole has been shown to prolong the QT interval in a dose-dependent manner and was also associated with a higher incidence of insomnia, headache, tremors, psychiatric disorders, and suicidal ideation in clinical trials; patients with pre-existing conditions or concomitant medications that could aggravate any of these effects should be treated with caution. In addition, fexinidazole has been associated with neutropenia and elevations in liver transaminases, which should be monitored. Nitroimidazoles like fexinidazole have been associated with a disulfiram-like reaction when used concomitantly with alcohol and psychotic reactions when taken with disulfiram itself; patients should avoid alcohol and disulfiram when taking fexinidazole. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense, with T. brucei gambiense HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage T. brucei gambiense HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal. Fexinidazole is the first all-oral treatment for T. brucei gambiense HAT. Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess in vitro activity against T. brucei gambiense, T. brucei rhodesiense, and T. brucei brucei in the 0.2-0.9 μg/mL range. Further studies revealed in vivo efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing nifurtimox / eflornithine combination therapy (NECT) in late-stage T. brucei gambiense infection. The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins. Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean C max and AUC last increased by 1.17 and 1.34, or by 1.5 and 1.61, when the dose was either doubled or tripled. Following absorption, fexinidazole is rapidly converted to its M1 metabolite, which undergoes a slower transformation to M2 over time. This is reflected in the T max of fexinidazole, M1, and M2 as 4 (0-9), 4 (0-6), and 6 (0-24) hours, respectively. In healthy adults given an 1800 mg loading dose followed by 1200 mg daily over 14 days, the mean C max for fexinidazole was 1.6 ± 0.4 μg/mL on day 1, 0.8 ± 0.3 μg/mL on day 2, and 0.5 ± 0.2 μg/mL on day 3. The relevant values for M1 were 8.1 ± 2.2, 8.0 ± 2.3, and 5.9 ± 2.1, while for M2 they were 7.5 ± 3.3, 19.6 ± 5.4, and 12.5 ± 3.5 μg/mL. Similarly, the AUC for fexinidazole was 14.3 ± 2.6, 11.6 ± 2.2, and 7.0 ± 2.5, for M1 was 102.3 ± 28.5, 127.9 ± 49.2, and 84.2 ± 36.3, and for M2 was 110.1 ± 41.1, 391.5 ± 126.7, and 252.4 ± 73.6 μg*h/mL. Concomitant food intake increases the C max and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios. There are no clear effects of age, renal, or hepatic impairment on absorption or plasma parameters of fexinidazole or its metabolites; further studies may be required to confirm/refute these observations. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fexinidazole is metabolized by a variety of enzymes including the CYP450 enzymes CYP1A2, 2B6, 2C19, 2D6, 3A4, and 3A5 as well as flavin mono-oxygenase-3 (FMO-3). Fexinidazole is first transformed to the sulfoxide M1 and then the sulfone M2, which does not appear to undergo further metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Elimination is almost entirely extra-renal; roughly 0.75-3.15% of a fexinidazole dose was recovered in urine over 168 h, primarily as M1 and M2 metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Healthy male adult volunteers were administered single or multiple daily doses of up to 3600 mg for 14 days and experienced elevated liver transaminases, vomiting, and panic attacks. Pediatric HAT patients given higher than recommended doses experienced vomiting, increased potassium, and decreased calcium levels. There is no specific antidote to fexinidazole; symptomatic and supportive measures are recommended in case of overdose. Rats and beagles given up to 800 mg/kg/day of fexinidazole showed mild appetite and body weight alterations but no clear hepatotoxicity. Fexinidazole did not induce any effects on embryo-fetal and postnatal development when administered to pregnant rats. Although fexinidazole is mutagenic in a standard Ames test, it is not anticipated to be genotoxic in humans. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fexinidazole is an orally bioavailable 2-substituted 5-nitroimidazole used to treat early- and late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense.

Coadministration of fexinidazole with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided. The severity of the interaction is moderate.

Question: Does Buserelin and Fexinidazole interact? Information: •Drug A: Buserelin •Drug B: Fexinidazole •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Buserelin is combined with Fexinidazole. •Extended Description: Coadministration of fexinidazole with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fexinidazole is a nitroimidazole indicated for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in patients 6 years of age and older weighing at least 20 kg. Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL), fexinidazole should only be used in these patients if there are no other available treatment options. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fexinidazole is a 2-substituted 5-nitroimidazole that is likely activated by parasitic nitroreductases to highly reactive species, leading to DNA and protein damage and eventual parasite death. The dosing schedule is designed to ensure a high enough concentration of fexinidazole and its reactive metabolites for at least 48 hours, which from in vitro studies was shown to be the minimum exposure time that was effectively trypanocidal. Although fexinidazole is effective in late-stage T. brucei gambiense HAT, it is less effective than NECT therapy in patients with severe (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL at baseline) disease. It should only be used in these patients if there are no other available treatment options. Fexinidazole has been shown to prolong the QT interval in a dose-dependent manner and was also associated with a higher incidence of insomnia, headache, tremors, psychiatric disorders, and suicidal ideation in clinical trials; patients with pre-existing conditions or concomitant medications that could aggravate any of these effects should be treated with caution. In addition, fexinidazole has been associated with neutropenia and elevations in liver transaminases, which should be monitored. Nitroimidazoles like fexinidazole have been associated with a disulfiram-like reaction when used concomitantly with alcohol and psychotic reactions when taken with disulfiram itself; patients should avoid alcohol and disulfiram when taking fexinidazole. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense, with T. brucei gambiense HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage T. brucei gambiense HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal. Fexinidazole is the first all-oral treatment for T. brucei gambiense HAT. Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess in vitro activity against T. brucei gambiense, T. brucei rhodesiense, and T. brucei brucei in the 0.2-0.9 μg/mL range. Further studies revealed in vivo efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing nifurtimox / eflornithine combination therapy (NECT) in late-stage T. brucei gambiense infection. The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins. Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean C max and AUC last increased by 1.17 and 1.34, or by 1.5 and 1.61, when the dose was either doubled or tripled. Following absorption, fexinidazole is rapidly converted to its M1 metabolite, which undergoes a slower transformation to M2 over time. This is reflected in the T max of fexinidazole, M1, and M2 as 4 (0-9), 4 (0-6), and 6 (0-24) hours, respectively. In healthy adults given an 1800 mg loading dose followed by 1200 mg daily over 14 days, the mean C max for fexinidazole was 1.6 ± 0.4 μg/mL on day 1, 0.8 ± 0.3 μg/mL on day 2, and 0.5 ± 0.2 μg/mL on day 3. The relevant values for M1 were 8.1 ± 2.2, 8.0 ± 2.3, and 5.9 ± 2.1, while for M2 they were 7.5 ± 3.3, 19.6 ± 5.4, and 12.5 ± 3.5 μg/mL. Similarly, the AUC for fexinidazole was 14.3 ± 2.6, 11.6 ± 2.2, and 7.0 ± 2.5, for M1 was 102.3 ± 28.5, 127.9 ± 49.2, and 84.2 ± 36.3, and for M2 was 110.1 ± 41.1, 391.5 ± 126.7, and 252.4 ± 73.6 μg*h/mL. Concomitant food intake increases the C max and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios. There are no clear effects of age, renal, or hepatic impairment on absorption or plasma parameters of fexinidazole or its metabolites; further studies may be required to confirm/refute these observations. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fexinidazole is metabolized by a variety of enzymes including the CYP450 enzymes CYP1A2, 2B6, 2C19, 2D6, 3A4, and 3A5 as well as flavin mono-oxygenase-3 (FMO-3). Fexinidazole is first transformed to the sulfoxide M1 and then the sulfone M2, which does not appear to undergo further metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Elimination is almost entirely extra-renal; roughly 0.75-3.15% of a fexinidazole dose was recovered in urine over 168 h, primarily as M1 and M2 metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Healthy male adult volunteers were administered single or multiple daily doses of up to 3600 mg for 14 days and experienced elevated liver transaminases, vomiting, and panic attacks. Pediatric HAT patients given higher than recommended doses experienced vomiting, increased potassium, and decreased calcium levels. There is no specific antidote to fexinidazole; symptomatic and supportive measures are recommended in case of overdose. Rats and beagles given up to 800 mg/kg/day of fexinidazole showed mild appetite and body weight alterations but no clear hepatotoxicity. Fexinidazole did not induce any effects on embryo-fetal and postnatal development when administered to pregnant rats. Although fexinidazole is mutagenic in a standard Ames test, it is not anticipated to be genotoxic in humans. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fexinidazole is an orally bioavailable 2-substituted 5-nitroimidazole used to treat early- and late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense. Output: Coadministration of fexinidazole with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided. The severity of the interaction is moderate.

Does Buserelin and Flecainide interact?

•Drug A: Buserelin •Drug B: Flecainide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Flecainide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In New Zealand and America, flecainide is indicated to prevent supraventricular arrhythmias and ventricular arrhythmias. In the United States, it is also indicated to prevent paroxysmal atrial fibrillation and flutter. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Flecainide inhibits the action of sodium and potassium ion channels in the heart, raising the threshold for depolarization and correcting arrhythmias. Flecainide has a long duration of action, allowing for once daily dosing. The therapeutic index is narrow. Patients should not take this medication if there is already structural heart disease or left ventricular systolic dysfunction. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Flecainide blocks fast inward sodium channels and slowly unbinds during diastole, prolonging the refractory period of the heart. This blockade also shortens the duration of action potentials through the Purkinjie fibers. Flecainide also prevents delayed rectifier potassium channels from opening, lengthening the action potential through ventricular and atrial muscle fibers. Finally, flecainide also blocks ryanodine receptor opening, reducing calcium release from sarcoplasmic reticulum, which reduces depolarization of cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral flecainide has a T max of 3-4h and a bioavialability of 90%. Taking flecainide with food or aluminum hydroxide antacids do not significantly affect the absorption of flecainide. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The average volume of distribution in 8 male subjects is 5.0-13.4L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Flecainide is 40% bound to protein in serum, mainly to alpha-1-acid glycoprotein and minorly to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Flecainide is mainly metabolized to meta-O-dealkylated flecainide or the meta-O-dealkylated lactam of flecainide. Meta-O-dealkylated flecainide has 20% the activity of flecainide. Both of these metabolites are generally detected as glucuronide or sulfate conjugates. Flecainide’s metabolism involves the action of CYP2D6 and CYP1A2. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 86% of a single oral dose is eliminated in the urine, with 42% as unchanged flecainide and 14% as meta-O-dealkylated flecainide, a similar amount of the meta-O-dealkylated lactam of flecainide, approximately 3% as an unidentified acid metabolite, and <1% as 2 other unknown metabolites. 5% is eliminated in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In healthy subjects, intravenous flecainide has an average half life of 13 hours for a single dose and 16 hours for multiple oral doses. In patients with a ventricular premature complex, flecainide has a half life of 20 hours. The half life of meta-O-dealkylated flecainide, a major metabolite of flecainide, is 12.6h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average clearance of intravenous flecainide is 4.6-12.1mL/min/kg in 8 male subjects. For oral flecainide, the clearance was 4-20mL/min/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in rats is 1346mg/kg and in mice is 170mg/kg. The subcutaneous LD 50 in rats is 215mg/kg and in mice is 188mg/kg. The oral TDLO in women is 20mg/kg and in men is 40mg/kg/2W. Patients experiencing an overdose may present with ECG abnormalities such as a lengthened PR interval, increased QRS duration, prolonged QT interval, increased amplitude of the T wave, reduced myocardial rate and contractility, hypotension, or death. Treat patients with symptomatic and supportive treatment which may involve administration of inotropic agents, assisted respiration, circulatory assistance, and acidification of the urine. Hemodialysis is not expected to be useful in the removal of flecainide from serum. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tambocor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flecaine Flecainida Flécaïnide Flecainide Flecainidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Flecainide is a class Ic antiarrhythmic agent used to manage atrial fibrillation and paroxysmal supraventricular tachycardias (PSVT).

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Flecainide interact? Information: •Drug A: Buserelin •Drug B: Flecainide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Flecainide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In New Zealand and America, flecainide is indicated to prevent supraventricular arrhythmias and ventricular arrhythmias. In the United States, it is also indicated to prevent paroxysmal atrial fibrillation and flutter. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Flecainide inhibits the action of sodium and potassium ion channels in the heart, raising the threshold for depolarization and correcting arrhythmias. Flecainide has a long duration of action, allowing for once daily dosing. The therapeutic index is narrow. Patients should not take this medication if there is already structural heart disease or left ventricular systolic dysfunction. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Flecainide blocks fast inward sodium channels and slowly unbinds during diastole, prolonging the refractory period of the heart. This blockade also shortens the duration of action potentials through the Purkinjie fibers. Flecainide also prevents delayed rectifier potassium channels from opening, lengthening the action potential through ventricular and atrial muscle fibers. Finally, flecainide also blocks ryanodine receptor opening, reducing calcium release from sarcoplasmic reticulum, which reduces depolarization of cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral flecainide has a T max of 3-4h and a bioavialability of 90%. Taking flecainide with food or aluminum hydroxide antacids do not significantly affect the absorption of flecainide. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The average volume of distribution in 8 male subjects is 5.0-13.4L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Flecainide is 40% bound to protein in serum, mainly to alpha-1-acid glycoprotein and minorly to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Flecainide is mainly metabolized to meta-O-dealkylated flecainide or the meta-O-dealkylated lactam of flecainide. Meta-O-dealkylated flecainide has 20% the activity of flecainide. Both of these metabolites are generally detected as glucuronide or sulfate conjugates. Flecainide’s metabolism involves the action of CYP2D6 and CYP1A2. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 86% of a single oral dose is eliminated in the urine, with 42% as unchanged flecainide and 14% as meta-O-dealkylated flecainide, a similar amount of the meta-O-dealkylated lactam of flecainide, approximately 3% as an unidentified acid metabolite, and <1% as 2 other unknown metabolites. 5% is eliminated in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In healthy subjects, intravenous flecainide has an average half life of 13 hours for a single dose and 16 hours for multiple oral doses. In patients with a ventricular premature complex, flecainide has a half life of 20 hours. The half life of meta-O-dealkylated flecainide, a major metabolite of flecainide, is 12.6h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average clearance of intravenous flecainide is 4.6-12.1mL/min/kg in 8 male subjects. For oral flecainide, the clearance was 4-20mL/min/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in rats is 1346mg/kg and in mice is 170mg/kg. The subcutaneous LD 50 in rats is 215mg/kg and in mice is 188mg/kg. The oral TDLO in women is 20mg/kg and in men is 40mg/kg/2W. Patients experiencing an overdose may present with ECG abnormalities such as a lengthened PR interval, increased QRS duration, prolonged QT interval, increased amplitude of the T wave, reduced myocardial rate and contractility, hypotension, or death. Treat patients with symptomatic and supportive treatment which may involve administration of inotropic agents, assisted respiration, circulatory assistance, and acidification of the urine. Hemodialysis is not expected to be useful in the removal of flecainide from serum. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tambocor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flecaine Flecainida Flécaïnide Flecainide Flecainidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Flecainide is a class Ic antiarrhythmic agent used to manage atrial fibrillation and paroxysmal supraventricular tachycardias (PSVT). Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Fluconazole interact?

•Drug A: Buserelin •Drug B: Fluconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Fluconazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fluconazole can be administered in the treatment of the following fungal infections: 1) Vaginal yeast infections caused by Candida 2) Systemic Candida infections 3) Both esophageal and oropharyngeal candidiasis 4) Cryptococcal meningitis 5) UTI (urinary tract infection) by Candida 6) Peritonitis (inflammation of the peritoneum) caused by Candida A note on fungal infection prophylaxis Patients receiving bone marrow transplantation who are treated with cytotoxic chemotherapy and/or radiation therapy may be predisposed to candida infections, and may receive fluconazole as prophylactic therapy. A note on laboratory testing Obtaining specimens for fungal culture and other important laboratory studies such as serology or pathology is advised before starting fluconazole therapy in order to isolate the organisms to be eliminated through treatment. It is permissible to start therapy before the results are available, however, adjusting the therapy once laboratory results confirm the causative organism may be necessary. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections: Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth as well as cell adhesion, thereby treating fungal infections and their symptoms. The fungistatic activity of fluconazole has also been shown in normal and immunocompromised animal models with both systemic and intracranial fungal infections caused by Cryptococcus neoformans and for systemic infections caused by Candida albicans. It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole. This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy. A note on steroidal effects of fluconazole There has been some concern that fluconazole may interfere with and inactivate human steroids/hormones due to the inhibition of hepatic cytochrome enzymes. Fluconazole has demonstrated to be more selective for fungal cytochrome P-450 enzymes than for a variety of mammalian cytochrome P-450 enzymes. Fluconazole 50 mg administered daily for up to 28 days in individuals of reproductive age has been show to have no effect on testosterone plasma concentrations of males and plasma concentrations of steroids in females. A 200-400 mg dose of fluconazole showed no clinically relevant effect on steroid levels or on ACTH-stimulated steroid response in healthy males, in one clinical study mentioned on the European Medicines Agency label. Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme normally works to convert lanosterol to ergosterol, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane. Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached. Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours. Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole. A note on the capsule and powder form and malabsorption syndromes The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, Lapp lactase enzyme deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and sucrase-isomaltase enzyme deficiency. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg. Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections. Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of fluconazole is low and estimated to be 11 to 12%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fluconazole is metabolized minimally in the liver. Fluconazole is an inhibitor of CYP2C9, CYP3A4 and CYP2C19. Two metabolites were detected in the urine of healthy volunteers taking a 50 mg radiolabeled dose of fluconazole; a glucuronidated metabolite on the hydroxyl moiety (6.5%) and a fluconazole N-oxide metabolite (2%). The same study indicated that no signs of metabolic cleavage of fluconazole were observed, suggesting a difference in metabolism when compared to other agents in the same drug class, which are heavily metabolized in the liver. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine. A note on renal failure The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single-dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients. •Clearance (Drug A): No clearance available •Clearance (Drug B): This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h). Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute oral toxicity (LD50): 1271 mg/kg (rat) Overdose information Fluconazole overdoses have been associated with hallucination and paranoia, sometimes in combination. In cases of overdose, employ supportive treatment. Gastric lavage may be necessary. Other modalities such as forced diuresis or hemodialysis may also be used. A note on liver toxicity The FDA label warns that this drug carries a risk of hepatotoxicity. Rare but serious cases of serious hepatic toxicity have been reported, especially in patients with serious underlying medical conditions using fluconazole. This group of patients has an increased risk of fatality when using fluconazole. In patients with existing liver dysfunction, use caution during fluconazole therapy. Those who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of increasingly severe injury to the liver. Fluconazole should be stopped if its use is likely to be the underlying cause of liver injury, and medical attention should be sought. Fluconazole induced hepatotoxicity is usually reversible. Carcinogenesis, mutagenesis, and impairment of fertility Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated orally for 24 months at doses equivalent to approximately 2-7 time the recommended human dose). Male rats given fluconazole at doses equivalent to supratherapeutic human doses showed an increased incidence of hepatocellular adenomas. Cytogenetic studies in vivo and in vitro demonstrated no sign of chromosomal mutation. The significance of these findings for humans is unknown. Use in pregnancy There are no sufficient and well-controlled studies of fluconazole use in pregnant women. Available human data do not show an increased risk of congenital anomalies after pregnant women were treated with standard doses (<200 mg/day) of fluconazole, either in a single dose or multiple doses in the first trimester did not appear to impact the fetus negatively. Several case reports describe rare but striking congenital anomalies observed in infants who were exposed to fluconazole at high doses reaching 400-800 mg/day, primarily in the first trimester of pregnancy. Similar findings were observed in animal studies. If this drug is administered during pregnancy, or if the patient becomes pregnant while taking fluconazole, the risk should be discussed thoroughly. Use in nursing Fluconazole is secreted in breastmilk at high concentrations. Exercise caution if this drug is used during nursing. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diflucan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluconazole is a triazole antifungal used to treat various fungal infections including candidiasis.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Fluconazole interact? Information: •Drug A: Buserelin •Drug B: Fluconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Fluconazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fluconazole can be administered in the treatment of the following fungal infections: 1) Vaginal yeast infections caused by Candida 2) Systemic Candida infections 3) Both esophageal and oropharyngeal candidiasis 4) Cryptococcal meningitis 5) UTI (urinary tract infection) by Candida 6) Peritonitis (inflammation of the peritoneum) caused by Candida A note on fungal infection prophylaxis Patients receiving bone marrow transplantation who are treated with cytotoxic chemotherapy and/or radiation therapy may be predisposed to candida infections, and may receive fluconazole as prophylactic therapy. A note on laboratory testing Obtaining specimens for fungal culture and other important laboratory studies such as serology or pathology is advised before starting fluconazole therapy in order to isolate the organisms to be eliminated through treatment. It is permissible to start therapy before the results are available, however, adjusting the therapy once laboratory results confirm the causative organism may be necessary. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections: Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth as well as cell adhesion, thereby treating fungal infections and their symptoms. The fungistatic activity of fluconazole has also been shown in normal and immunocompromised animal models with both systemic and intracranial fungal infections caused by Cryptococcus neoformans and for systemic infections caused by Candida albicans. It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole. This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy. A note on steroidal effects of fluconazole There has been some concern that fluconazole may interfere with and inactivate human steroids/hormones due to the inhibition of hepatic cytochrome enzymes. Fluconazole has demonstrated to be more selective for fungal cytochrome P-450 enzymes than for a variety of mammalian cytochrome P-450 enzymes. Fluconazole 50 mg administered daily for up to 28 days in individuals of reproductive age has been show to have no effect on testosterone plasma concentrations of males and plasma concentrations of steroids in females. A 200-400 mg dose of fluconazole showed no clinically relevant effect on steroid levels or on ACTH-stimulated steroid response in healthy males, in one clinical study mentioned on the European Medicines Agency label. Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme normally works to convert lanosterol to ergosterol, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane. Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached. Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours. Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole. A note on the capsule and powder form and malabsorption syndromes The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, Lapp lactase enzyme deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and sucrase-isomaltase enzyme deficiency. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg. Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections. Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of fluconazole is low and estimated to be 11 to 12%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fluconazole is metabolized minimally in the liver. Fluconazole is an inhibitor of CYP2C9, CYP3A4 and CYP2C19. Two metabolites were detected in the urine of healthy volunteers taking a 50 mg radiolabeled dose of fluconazole; a glucuronidated metabolite on the hydroxyl moiety (6.5%) and a fluconazole N-oxide metabolite (2%). The same study indicated that no signs of metabolic cleavage of fluconazole were observed, suggesting a difference in metabolism when compared to other agents in the same drug class, which are heavily metabolized in the liver. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine. A note on renal failure The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single-dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients. •Clearance (Drug A): No clearance available •Clearance (Drug B): This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h). Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute oral toxicity (LD50): 1271 mg/kg (rat) Overdose information Fluconazole overdoses have been associated with hallucination and paranoia, sometimes in combination. In cases of overdose, employ supportive treatment. Gastric lavage may be necessary. Other modalities such as forced diuresis or hemodialysis may also be used. A note on liver toxicity The FDA label warns that this drug carries a risk of hepatotoxicity. Rare but serious cases of serious hepatic toxicity have been reported, especially in patients with serious underlying medical conditions using fluconazole. This group of patients has an increased risk of fatality when using fluconazole. In patients with existing liver dysfunction, use caution during fluconazole therapy. Those who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of increasingly severe injury to the liver. Fluconazole should be stopped if its use is likely to be the underlying cause of liver injury, and medical attention should be sought. Fluconazole induced hepatotoxicity is usually reversible. Carcinogenesis, mutagenesis, and impairment of fertility Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated orally for 24 months at doses equivalent to approximately 2-7 time the recommended human dose). Male rats given fluconazole at doses equivalent to supratherapeutic human doses showed an increased incidence of hepatocellular adenomas. Cytogenetic studies in vivo and in vitro demonstrated no sign of chromosomal mutation. The significance of these findings for humans is unknown. Use in pregnancy There are no sufficient and well-controlled studies of fluconazole use in pregnant women. Available human data do not show an increased risk of congenital anomalies after pregnant women were treated with standard doses (<200 mg/day) of fluconazole, either in a single dose or multiple doses in the first trimester did not appear to impact the fetus negatively. Several case reports describe rare but striking congenital anomalies observed in infants who were exposed to fluconazole at high doses reaching 400-800 mg/day, primarily in the first trimester of pregnancy. Similar findings were observed in animal studies. If this drug is administered during pregnancy, or if the patient becomes pregnant while taking fluconazole, the risk should be discussed thoroughly. Use in nursing Fluconazole is secreted in breastmilk at high concentrations. Exercise caution if this drug is used during nursing. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diflucan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluconazole is a triazole antifungal used to treat various fungal infections including candidiasis. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Fluorouracil interact?

•Drug A: Buserelin •Drug B: Fluorouracil •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Fluorouracil. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): 28-100% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 8-12% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10-20 minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =230mg/kg (orally in mice) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actikerall, Carac, Efudex, Fluoroplex, Tolak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Fluoracil 5-Fluorouracil 5-Fluracil 5-FU Fluoro Uracil Fluorouracil Fluorouracilo Fluorouracilum Fluouracil •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluorouracil is a pyrimidine analog used to treat basal cell carcinomas, and as an injection in palliative cancer treatment.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Fluorouracil interact? Information: •Drug A: Buserelin •Drug B: Fluorouracil •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Fluorouracil. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): 28-100% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 8-12% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10-20 minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =230mg/kg (orally in mice) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actikerall, Carac, Efudex, Fluoroplex, Tolak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Fluoracil 5-Fluorouracil 5-Fluracil 5-FU Fluoro Uracil Fluorouracil Fluorouracilo Fluorouracilum Fluouracil •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluorouracil is a pyrimidine analog used to treat basal cell carcinomas, and as an injection in palliative cancer treatment. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Fluoxetine interact?

•Drug A: Buserelin •Drug B: Fluoxetine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Fluoxetine is combined with Buserelin. •Extended Description: The risk of QTc prolongation associated with fluoxetine increases in the presence of additional risk factors.2 It is known that the administration of multiple QTc prolonging agents increases the risk for drug-induced QTc prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fluoxetine is indicated for both acute and maintenance treatment of major depressive disorder, obsessive compulsive disorder, and bulimia nervosa; however, it is only indicated for acute treatment of panic disorder independent of whether agoraphobia is present. Fluoxetine may also be used in combination with olanzapine to treat depression related to Bipolar I Disorder, and treatment resistant depression. Fluoxetine is additionally indicated for the treatment of female patients with premenstrual dysphoric disorder (PMDD). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT 2C receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 94% of fluoxetine is plasma protein bound. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fluoxetine is primarily eliminated in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In a report that included 234 fluoxetine overdose cases, it was concluded that symptoms resulting from fluoxetine overdose were generally minor and short in duration. The most common overdose adverse effects included drowsiness, tremor, tachycardia, nausea and vomiting, and providing the patient with aggressive supportive care was the recommended intervention. Despite this evidence, more severe adverse effects have been linked to fluoxetine ingestion although most of these reports involved co-ingestion with other substances or drugs as well as other factors. For example, there is a case report that details a patient who ingested 1400 mg of fluoxetine in a suicide attempt and as a result, experienced a generalized seizure three hours later. In a separate case, a 14 year old patient ingested 1.2 g of fluoxetine and subsequently experienced tonic/clonic seizures, symptoms consistent with serotonin syndrome, and rhabdomyolysis, although the patient did not experience sustained renal injury. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Prozac, Sarafem, Symbyax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxetin Fluoxetina Fluoxétine Fluoxetine Fluoxetinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluoxetine is a selective serotonin reuptake inhibitor used to treat major depressive disorder, bulimia, OCD, premenstrual dysphoric disorder, panic disorder, and bipolar I.

The risk of QTc prolongation associated with fluoxetine increases in the presence of additional risk factors.2 It is known that the administration of multiple QTc prolonging agents increases the risk for drug-induced QTc prolongation. The severity of the interaction is moderate.

Question: Does Buserelin and Fluoxetine interact? Information: •Drug A: Buserelin •Drug B: Fluoxetine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Fluoxetine is combined with Buserelin. •Extended Description: The risk of QTc prolongation associated with fluoxetine increases in the presence of additional risk factors.2 It is known that the administration of multiple QTc prolonging agents increases the risk for drug-induced QTc prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fluoxetine is indicated for both acute and maintenance treatment of major depressive disorder, obsessive compulsive disorder, and bulimia nervosa; however, it is only indicated for acute treatment of panic disorder independent of whether agoraphobia is present. Fluoxetine may also be used in combination with olanzapine to treat depression related to Bipolar I Disorder, and treatment resistant depression. Fluoxetine is additionally indicated for the treatment of female patients with premenstrual dysphoric disorder (PMDD). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT 2C receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 94% of fluoxetine is plasma protein bound. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fluoxetine is primarily eliminated in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In a report that included 234 fluoxetine overdose cases, it was concluded that symptoms resulting from fluoxetine overdose were generally minor and short in duration. The most common overdose adverse effects included drowsiness, tremor, tachycardia, nausea and vomiting, and providing the patient with aggressive supportive care was the recommended intervention. Despite this evidence, more severe adverse effects have been linked to fluoxetine ingestion although most of these reports involved co-ingestion with other substances or drugs as well as other factors. For example, there is a case report that details a patient who ingested 1400 mg of fluoxetine in a suicide attempt and as a result, experienced a generalized seizure three hours later. In a separate case, a 14 year old patient ingested 1.2 g of fluoxetine and subsequently experienced tonic/clonic seizures, symptoms consistent with serotonin syndrome, and rhabdomyolysis, although the patient did not experience sustained renal injury. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Prozac, Sarafem, Symbyax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxetin Fluoxetina Fluoxétine Fluoxetine Fluoxetinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluoxetine is a selective serotonin reuptake inhibitor used to treat major depressive disorder, bulimia, OCD, premenstrual dysphoric disorder, panic disorder, and bipolar I. Output: The risk of QTc prolongation associated with fluoxetine increases in the presence of additional risk factors.2 It is known that the administration of multiple QTc prolonging agents increases the risk for drug-induced QTc prolongation. The severity of the interaction is moderate.

Does Buserelin and Flupentixol interact?

•Drug A: Buserelin •Drug B: Flupentixol •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Flupentixol. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Flupentixol is indicated for maintenance therapy of chronic schizophrenic patients whose main manifestations do not include excitement, agitation or hyperactivity. It is indicated for the management of depression in adult patients who may, or may not, also be showing signs of anxiety. Flupentixol in combination with melitracen is indicated to manage symptoms of anxiety, depression, and asthenia in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Flupentixol is an antipsychotic agent with anxiolytic and mild sedative actions. It exerts weak anticholinergic and adrenergic effects. It possesses antiemetic actions. As flupentixol works by antagonizing dopamine actions, it can cause extrapyramidal effects, mostly at doses greater than 10 mg. In clinical trials, flupentixol-induced extrapyramidal effects have been managed with anti-Parkinsonian drugs. Drug esterification in the intramuscular formulation of the drug results in slow release of the drug from the injection site and a prolonged duration of action. Flupentixol has been investigated for use in mild to moderate depression: compared to other antidepressant agents, flupentixol has a rapid onset of action, where antidepressive effects were observed within the first two to three days after administration. As with other antipsychotic agents, flupentixol can cause QTc prolongation and increase the risk of arrhythmias. In clinical trials, flupentixol was associated with the risk of cardiovascular disease, cerebrovascular adverse events, stroke, and venous thromboembolism. Flupentixol can elevate the levels of prolactin; however, the clinical significance of hyperprolactinemia caused by neuroleptic drugs is unclear. Long-term hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects. Interestingly, recent studies show that flupentixol exhibits anti-tumour properties alone or synergistically with other anticancer drugs like gefitinib. One study demonstrated that in vitro, flupentixol docks to the ATP binding pocket of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that activates signalling pathways that are often hyperactivated in some cancers. Flupentixol inhibited the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of flupentixol is not completely understood. The antipsychotic actions are mainly thought to arise from cis(Z)-flupentixol, the active stereoisomer, acting as an antagonist at both dopamine D 1 and D 2 receptors with equal affinities. Schizophrenia is a mental illness characterized by positive (such as hallucinations and delusions) and negative (such as affect flattening and apathy) symptoms. While several neurotransmitter systems are implicated in the pathophysiologic processes leading to the development of symptoms, the dopamine and glutamate systems have been extensively studied. It is generally understood that positive symptoms of schizophrenia arise from a dysregulated striatal dopamine pathway, leading to hyperstimulation of D 2 receptors. Many antipsychotic agents work by blocking D 2 receptors as antagonists; similarly, cis(Z)-flupentixol, the active stereoisomer, is an antagonist at D 2 receptors. However, there is now evidence that antipsychotic agents can work by blocking other dopamine receptor subtypes, such as D 1, D 3, or D 4 receptors. One study showed that cis(Z)-flupentixol is an antagonist at both dopamine D 1 and D 2 receptors with equal affinities, and binds to D3 and D4 receptors with lower affinities. It also binds to alpha-1 adrenoceptors. Antidepressant effects of flupentixol are understood to be mediated by antagonism at 5-HT 2A receptors, which are commonly downregulated following repeated antidepressant treatment. Flupentixol also binds to 5-HT 2C receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. T max ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L). From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain. •Protein binding (Drug A): 15% •Protein binding (Drug B): Flupentixol is 99% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Flupentixol is metabolized in the liver via sulfoxidation, dealkylation, and glucuronidation to form pharmacologically inactive metabolites. Flupentixol decanoate, the active ingredient in the intramuscular formulation, is hydrolyzed to flupentixol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupentixol is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life is about 35 hours following oral administration and three weeks following intramuscular administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following oral administration, the mean systemic clearance is about 0.29 L/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 423 mg/kg in mice and 791 mg/kg in rats. The intravenous LD 50 is 37 mg/kg in rats. Flupentixol overdose is characterized by sedation, frequently preceded by extreme agitation, excitement, confusion, somnolence, coma, convulsions, and hyperthermia or hypothermia. Extrapyramidal symptoms or respiratory and circulatory collapse may be observed. ECG changes, QT prolongation, Torsades de Pointes, cardiac arrest and ventricular arrhythmias have been reported from the combined use of drugs known to affect the heart with large doses of flupentixol. In case of overdose, symptomatic treatment should be initiated with airway management. In case of severe hypotension, epinephrine should not be used: instead, intravenous vasopressor drugs, such as levarterenol, can be used. Antiparkinsonian medication should be administered only if extrapyramidal symptoms develop. Gastric lavage should be initiated in the case of flupentixol tablet overdose. Further injections of flupentixol should be discontinued in case of an intramuscularly-administered drug overdose until the patient shows signs of relapse, in which the dosage can subsequently be decreased. Neuroleptic malignant syndrome is associated with neuroleptic drugs, which should be responded to with immediate discontinuation of the drug and initiation of symptomatic treatment and medical monitoring. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Fluanxol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Flupentixol is a thioxanthene neuroleptic used to treat schizophrenia and depression.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Flupentixol interact? Information: •Drug A: Buserelin •Drug B: Flupentixol •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Flupentixol. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Flupentixol is indicated for maintenance therapy of chronic schizophrenic patients whose main manifestations do not include excitement, agitation or hyperactivity. It is indicated for the management of depression in adult patients who may, or may not, also be showing signs of anxiety. Flupentixol in combination with melitracen is indicated to manage symptoms of anxiety, depression, and asthenia in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Flupentixol is an antipsychotic agent with anxiolytic and mild sedative actions. It exerts weak anticholinergic and adrenergic effects. It possesses antiemetic actions. As flupentixol works by antagonizing dopamine actions, it can cause extrapyramidal effects, mostly at doses greater than 10 mg. In clinical trials, flupentixol-induced extrapyramidal effects have been managed with anti-Parkinsonian drugs. Drug esterification in the intramuscular formulation of the drug results in slow release of the drug from the injection site and a prolonged duration of action. Flupentixol has been investigated for use in mild to moderate depression: compared to other antidepressant agents, flupentixol has a rapid onset of action, where antidepressive effects were observed within the first two to three days after administration. As with other antipsychotic agents, flupentixol can cause QTc prolongation and increase the risk of arrhythmias. In clinical trials, flupentixol was associated with the risk of cardiovascular disease, cerebrovascular adverse events, stroke, and venous thromboembolism. Flupentixol can elevate the levels of prolactin; however, the clinical significance of hyperprolactinemia caused by neuroleptic drugs is unclear. Long-term hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects. Interestingly, recent studies show that flupentixol exhibits anti-tumour properties alone or synergistically with other anticancer drugs like gefitinib. One study demonstrated that in vitro, flupentixol docks to the ATP binding pocket of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that activates signalling pathways that are often hyperactivated in some cancers. Flupentixol inhibited the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of flupentixol is not completely understood. The antipsychotic actions are mainly thought to arise from cis(Z)-flupentixol, the active stereoisomer, acting as an antagonist at both dopamine D 1 and D 2 receptors with equal affinities. Schizophrenia is a mental illness characterized by positive (such as hallucinations and delusions) and negative (such as affect flattening and apathy) symptoms. While several neurotransmitter systems are implicated in the pathophysiologic processes leading to the development of symptoms, the dopamine and glutamate systems have been extensively studied. It is generally understood that positive symptoms of schizophrenia arise from a dysregulated striatal dopamine pathway, leading to hyperstimulation of D 2 receptors. Many antipsychotic agents work by blocking D 2 receptors as antagonists; similarly, cis(Z)-flupentixol, the active stereoisomer, is an antagonist at D 2 receptors. However, there is now evidence that antipsychotic agents can work by blocking other dopamine receptor subtypes, such as D 1, D 3, or D 4 receptors. One study showed that cis(Z)-flupentixol is an antagonist at both dopamine D 1 and D 2 receptors with equal affinities, and binds to D3 and D4 receptors with lower affinities. It also binds to alpha-1 adrenoceptors. Antidepressant effects of flupentixol are understood to be mediated by antagonism at 5-HT 2A receptors, which are commonly downregulated following repeated antidepressant treatment. Flupentixol also binds to 5-HT 2C receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. T max ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L). From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain. •Protein binding (Drug A): 15% •Protein binding (Drug B): Flupentixol is 99% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Flupentixol is metabolized in the liver via sulfoxidation, dealkylation, and glucuronidation to form pharmacologically inactive metabolites. Flupentixol decanoate, the active ingredient in the intramuscular formulation, is hydrolyzed to flupentixol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupentixol is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life is about 35 hours following oral administration and three weeks following intramuscular administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following oral administration, the mean systemic clearance is about 0.29 L/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 423 mg/kg in mice and 791 mg/kg in rats. The intravenous LD 50 is 37 mg/kg in rats. Flupentixol overdose is characterized by sedation, frequently preceded by extreme agitation, excitement, confusion, somnolence, coma, convulsions, and hyperthermia or hypothermia. Extrapyramidal symptoms or respiratory and circulatory collapse may be observed. ECG changes, QT prolongation, Torsades de Pointes, cardiac arrest and ventricular arrhythmias have been reported from the combined use of drugs known to affect the heart with large doses of flupentixol. In case of overdose, symptomatic treatment should be initiated with airway management. In case of severe hypotension, epinephrine should not be used: instead, intravenous vasopressor drugs, such as levarterenol, can be used. Antiparkinsonian medication should be administered only if extrapyramidal symptoms develop. Gastric lavage should be initiated in the case of flupentixol tablet overdose. Further injections of flupentixol should be discontinued in case of an intramuscularly-administered drug overdose until the patient shows signs of relapse, in which the dosage can subsequently be decreased. Neuroleptic malignant syndrome is associated with neuroleptic drugs, which should be responded to with immediate discontinuation of the drug and initiation of symptomatic treatment and medical monitoring. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Fluanxol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Flupentixol is a thioxanthene neuroleptic used to treat schizophrenia and depression. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Fluspirilene interact?

•Drug A: Buserelin •Drug B: Fluspirilene •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Fluspirilene. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used for the treatment of schizophrenia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluspirilene is a relatively long-acting injectable depot antipsychotic drug used for schizophrenia. Fluspirilene does not differ greatly from other depot antipsychotics (fluphenazine decanoate, fluphenazine enathate, perphenazine onanthat, pipotiazine undecylenate) with respect to treatment efficacy, response or tolerability. Outcomes suggest that fluspirilene does not differ significantly from oral antipsychotics or in different weekly regimens, although much cannot be inferred because of the shortage of trials. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluspirilene is an antipsychotic agent used in the treatment of schizophrenia.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Fluspirilene interact? Information: •Drug A: Buserelin •Drug B: Fluspirilene •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Fluspirilene. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used for the treatment of schizophrenia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Fluspirilene is a relatively long-acting injectable depot antipsychotic drug used for schizophrenia. Fluspirilene does not differ greatly from other depot antipsychotics (fluphenazine decanoate, fluphenazine enathate, perphenazine onanthat, pipotiazine undecylenate) with respect to treatment efficacy, response or tolerability. Outcomes suggest that fluspirilene does not differ significantly from oral antipsychotics or in different weekly regimens, although much cannot be inferred because of the shortage of trials. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fluspirilene is an antipsychotic agent used in the treatment of schizophrenia. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Formoterol interact?

•Drug A: Buserelin •Drug B: Formoterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Formoterol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Formoterol is indicated in various formulations for the treatment of asthma and COPD. For the treatment of COPD, formoterol is available as a single-entity inhalation solution, in combination with the long-acting muscarinic antagonists (LAMAs) aclidinium and glycopyrronium, and in combination with the corticosteroid budesonide. For the treatment of asthma, formoterol is available in combination with mometasone furoate for patients 5 years and older and with budesonide for patients 6 years and older. Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Formoterol is a relatively selective long-acting agonist of beta 2 -adrenergic receptors, although it does carry some degree of activity at beta 1 and beta 3 receptors. Beta 2 receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta 1 receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta 2 receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta 2 receptors over beta 1 receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut). Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C max and AUC 0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C max and AUC 0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding to serum albumin in vitro is approximately 31%-38% over a plasma concentration range of 5-500 ng/mL - it should be noted, however, that these concentrations are higher than that seen following inhalation. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. In vitro studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance of formoterol following inhalation is approximately 157 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in rats is 3130 mg/kg. Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bevespi, Breyna, Breztri, Duaklir, Duaklir Genuair, Dulera, Foradil, Oxeze, Perforomist, Symbicort, Zenhale •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Formoterol Formoterolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Formoterol is an inhaled long-acting beta2-adrenergic receptor agonist used as a bronchodilator in the management of asthma and COPD.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Formoterol interact? Information: •Drug A: Buserelin •Drug B: Formoterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Formoterol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Formoterol is indicated in various formulations for the treatment of asthma and COPD. For the treatment of COPD, formoterol is available as a single-entity inhalation solution, in combination with the long-acting muscarinic antagonists (LAMAs) aclidinium and glycopyrronium, and in combination with the corticosteroid budesonide. For the treatment of asthma, formoterol is available in combination with mometasone furoate for patients 5 years and older and with budesonide for patients 6 years and older. Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Formoterol is a relatively selective long-acting agonist of beta 2 -adrenergic receptors, although it does carry some degree of activity at beta 1 and beta 3 receptors. Beta 2 receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta 1 receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta 2 receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta 2 receptors over beta 1 receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut). Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C max and AUC 0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C max and AUC 0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding to serum albumin in vitro is approximately 31%-38% over a plasma concentration range of 5-500 ng/mL - it should be noted, however, that these concentrations are higher than that seen following inhalation. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. In vitro studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance of formoterol following inhalation is approximately 157 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in rats is 3130 mg/kg. Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bevespi, Breyna, Breztri, Duaklir, Duaklir Genuair, Dulera, Foradil, Oxeze, Perforomist, Symbicort, Zenhale •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Formoterol Formoterolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Formoterol is an inhaled long-acting beta2-adrenergic receptor agonist used as a bronchodilator in the management of asthma and COPD. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Foscarnet interact?

•Drug A: Buserelin •Drug B: Foscarnet •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Foscarnet is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) and for treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits replication of herpes viruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to foscarnet. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to foscarnet and may not respond to therapy with foscarnet. The combination of foscarnet and ganciclovir has been shown to have enhanced activity in vitro. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Foscarnet exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Poorly absorbed after oral administration (bioavailability from 12 to 22%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 14-17% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Not metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 3.3-6.8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 2.13 +/- 0.71 mL/min/kg [patients had normal renal function (CrCl > 80 mL/min] 68 +/- 8 mL/min/kg [CrCl was 50-80 mL/min] 34 +/- 9 mL/min/kg [CrCl was 25-49 mL/min] 20 +/- 4 mL/min/kg [CrCl was 10 - 24 mL/min] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral, rat LD 50: >2,000 mg/kg. Signs of overdose include renal impairment. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Foscavir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Foscarnet is an antiviral used to treat CMV, HIV, and HSV infections.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Foscarnet interact? Information: •Drug A: Buserelin •Drug B: Foscarnet •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Foscarnet is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) and for treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits replication of herpes viruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to foscarnet. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to foscarnet and may not respond to therapy with foscarnet. The combination of foscarnet and ganciclovir has been shown to have enhanced activity in vitro. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Foscarnet exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Poorly absorbed after oral administration (bioavailability from 12 to 22%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 14-17% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Not metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 3.3-6.8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 2.13 +/- 0.71 mL/min/kg [patients had normal renal function (CrCl > 80 mL/min] 68 +/- 8 mL/min/kg [CrCl was 50-80 mL/min] 34 +/- 9 mL/min/kg [CrCl was 25-49 mL/min] 20 +/- 4 mL/min/kg [CrCl was 10 - 24 mL/min] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral, rat LD 50: >2,000 mg/kg. Signs of overdose include renal impairment. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Foscavir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Foscarnet is an antiviral used to treat CMV, HIV, and HSV infections. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Fostemsavir interact?

•Drug A: Buserelin •Drug B: Fostemsavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Fostemsavir. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fostemsavir is indicated, in combination with other antiretrovirals, for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults failing their current antiretroviral therapy due to resistance, intolerance, or safety concerns. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Temsavir inhibits the first stage in the HIV-1 viral lifecycle: attachment. It has a moderate duration of action necessitating twice-daily dosing. Fostemsavir, administered at roughly 4x the recommended human dose, has been observed to significantly prolong the QTc-interval. Patients with a history of QTc-prolongation, those receiving other QTc-prolonging medications, and/or those with pre-existing cardiac disease should use fostemsavir with caution, and should be monitored at baseline and throughout therapy for signs or symptoms suggestive of QTc-prolongation. Fostemsavir should also be used with caution in patients with hepatitis B or C co-infection as elevations in hepatic transaminases were observed in greater proportions in these populations in clinical trials. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The gp120 subunit within the gp160 envelope glycoprotein of HIV-1 is a new and novel target in the treatment of HIV-1 infection. These subunits are responsible for facilitating the first step in the viral life cycle, attachment, by mediating the interaction between the virus and host cell CD4 receptors. Following attachment, HIV-1 undergoes assembly, budding, and maturation within the host cell, after which mature viral particles are released to continue the viral life cycle. Fostemsavir's active metabolite, temsavir, is an HIV-1 attachment inhibitor. It binds directly to the gp120 subunit to inhibit viral interaction with host CD4 receptors, thereby preventing the initial attachment required for viral replication. It has also been shown to inhibit other gp120-dependent post-attachment steps required for viral entry. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration. Fostemsavir, a phosphonooxymethyl prodrug of temsavir, has improved aqueous solubility and stability under acidic conditions as compared to its parent drug - following oral administration of fostemsavir, the absolute bioavailability is approximately 26.9%. The C max and AUC tau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a T max of approximately 2 hours. Co-administration of fostemsavir with a standard meal increases its AUC by approximately 10%, while co-administration with a high-fat meal increases its AUC by approximately 81%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Temsavir is approximately 88.4% protein-bound in plasma, primarily to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen. Temsavir undergoes further biotransformation to two predominant inactive metabolites: BMS-646915, a product of hydrolysis by esterases, and BMS-930644, an N-dealkylated metabolite generated via oxidation by CYP3A4. Approximately 36.1% of an administered oral dose is metabolized by esterases, 21.2% is metabolized by CYP3A4, and <1% is conjugated by UDP-glucuronosyltransferases (UGT) prior to elimination. Both temsavir and its two predominant metabolites are known to inhibit BCRP. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites. Approximately 51% of a given dose is excreted in the urine, with <2% comprising unchanged parent drug, and 33% is excreted in the feces, of which 1.1% is unchanged parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life of temsavir is approximately 11 hours. Fostemsavir is generally undetectable in plasma following oral administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance and apparent clearance of temsavir, the active metabolite of fostemsavir, are 17.9 L/h and 66.4 L/h, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Data regarding fostemsavir overdose are unavailable. Symptoms of overdose are likely to be consistent with fostemsavir's adverse effect profile and may therefore involve significant GI disturbance and prolongation of the QT interval. In the event of overdose, patients should be monitored closely, including the use of ECG, and treated symptomatically as clinically indicated. As fostemsavir is highly protein-bound, dialysis is unlikely to be of benefit in the event of an overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rukobia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fostemsavir is an antiretroviral HIV-1 attachment inhibitor targeted against the gp120 subunit within the HIV-1 gp160 envelope glycoprotein.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Fostemsavir interact? Information: •Drug A: Buserelin •Drug B: Fostemsavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Fostemsavir. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Fostemsavir is indicated, in combination with other antiretrovirals, for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults failing their current antiretroviral therapy due to resistance, intolerance, or safety concerns. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Temsavir inhibits the first stage in the HIV-1 viral lifecycle: attachment. It has a moderate duration of action necessitating twice-daily dosing. Fostemsavir, administered at roughly 4x the recommended human dose, has been observed to significantly prolong the QTc-interval. Patients with a history of QTc-prolongation, those receiving other QTc-prolonging medications, and/or those with pre-existing cardiac disease should use fostemsavir with caution, and should be monitored at baseline and throughout therapy for signs or symptoms suggestive of QTc-prolongation. Fostemsavir should also be used with caution in patients with hepatitis B or C co-infection as elevations in hepatic transaminases were observed in greater proportions in these populations in clinical trials. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The gp120 subunit within the gp160 envelope glycoprotein of HIV-1 is a new and novel target in the treatment of HIV-1 infection. These subunits are responsible for facilitating the first step in the viral life cycle, attachment, by mediating the interaction between the virus and host cell CD4 receptors. Following attachment, HIV-1 undergoes assembly, budding, and maturation within the host cell, after which mature viral particles are released to continue the viral life cycle. Fostemsavir's active metabolite, temsavir, is an HIV-1 attachment inhibitor. It binds directly to the gp120 subunit to inhibit viral interaction with host CD4 receptors, thereby preventing the initial attachment required for viral replication. It has also been shown to inhibit other gp120-dependent post-attachment steps required for viral entry. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration. Fostemsavir, a phosphonooxymethyl prodrug of temsavir, has improved aqueous solubility and stability under acidic conditions as compared to its parent drug - following oral administration of fostemsavir, the absolute bioavailability is approximately 26.9%. The C max and AUC tau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a T max of approximately 2 hours. Co-administration of fostemsavir with a standard meal increases its AUC by approximately 10%, while co-administration with a high-fat meal increases its AUC by approximately 81%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Temsavir is approximately 88.4% protein-bound in plasma, primarily to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen. Temsavir undergoes further biotransformation to two predominant inactive metabolites: BMS-646915, a product of hydrolysis by esterases, and BMS-930644, an N-dealkylated metabolite generated via oxidation by CYP3A4. Approximately 36.1% of an administered oral dose is metabolized by esterases, 21.2% is metabolized by CYP3A4, and <1% is conjugated by UDP-glucuronosyltransferases (UGT) prior to elimination. Both temsavir and its two predominant metabolites are known to inhibit BCRP. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites. Approximately 51% of a given dose is excreted in the urine, with <2% comprising unchanged parent drug, and 33% is excreted in the feces, of which 1.1% is unchanged parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life of temsavir is approximately 11 hours. Fostemsavir is generally undetectable in plasma following oral administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance and apparent clearance of temsavir, the active metabolite of fostemsavir, are 17.9 L/h and 66.4 L/h, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Data regarding fostemsavir overdose are unavailable. Symptoms of overdose are likely to be consistent with fostemsavir's adverse effect profile and may therefore involve significant GI disturbance and prolongation of the QT interval. In the event of overdose, patients should be monitored closely, including the use of ECG, and treated symptomatically as clinically indicated. As fostemsavir is highly protein-bound, dialysis is unlikely to be of benefit in the event of an overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rukobia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Fostemsavir is an antiretroviral HIV-1 attachment inhibitor targeted against the gp120 subunit within the HIV-1 gp160 envelope glycoprotein. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Gadobenic acid interact?

•Drug A: Buserelin •Drug B: Gadobenic acid •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Gadobenic acid. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Gadobenate dimeglumine is indicated for use in magnetic resonance imaging (MRI) of the central nervous system in adult and pediatric patients in order to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. It is also indicated for use in magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Unlike other paramagnetic contrast agents, gadobenate dimeglumine demonstrates weak and transient interactions with serum proteins that cause slowing in the molecular tumbling dynamics, resulting in strong increases in relaxivity in solutions containing serum proteins. The improved relaxation effect can contribute to increased contrast-to-noise ratio and lesion-to-brain ratio, which may improve visualization. Disruption of the blood-brain barrier or abnormal vascularity allows enhancement by gadobenate dimeglumine of lesions such as neoplasms, abscesses, and infarcts. Uptake of gadobenate dimeglumine into hepatocytes has been demonstrated. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The large magnetic moment produced by the paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue. In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At recommended doses, the effect is observed with the greatest sensitivity in the T1-weighted sequences. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Three single-dose intravenous studies were conducted in 32 healthy male subjects to assess the pharmacokinetics of gadobenate dimeglumine. The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg. Upon injection, the meglumine salt is completely dissociated from the gadobenate dimeglumine complex. Thus, the pharmacokinetics is based on the assay of gadobenate ion, the MRI contrast effective ion in gadobenate dimeglumine. Data for plasma concentration and area under the curve demonstrated linear dependence on the administered dose. The pharmacokinetics of gadobenate ion following intravenous administration can be best described using a two-compartment model. A population pharmacokinetic analysis incorporated data from 25 healthy subjects (14 males and 11 females) and 15 subjects undergoing MR imaging of the central nervous system (7 males and 8 females) between ages of 2 and 16 years. The subjects received a single intravenous dose of 0.1 mmol/kg of gadobenate dimeglumine. The geometric mean C max was 62.3 µg/mL (n=16) in children 2 to 5 years of age, and 64.2 µg/mL (n=24) in children older than 5 years. The geometric mean AUC 0-∞ was 77.9 μg⋅h/mL in children 2-5 years of age (n=16) and 82.6 μg⋅h/mL in children older than 5 years (n=24). The geometric mean half-life was 1.2 hours in children 2 to 5 years of age and 0.93 hours in children older than 5 years. There was no significant gender-related difference in the pharmacokinetic parameters in the pediatric patients. Pharmacokinetic simulations indicate similar AUC and Cmax values for gadobenate dimeglumine in pediatric subjects less than 2 years when compared to those reported for adults; no age-based dose adjustment is necessary for this pediatric population. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of the central compartment ranged from 0.074 ± 0.017 to 0.158 ± 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170 ± 0.016 to 0.282 ± 0.079 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Although in vitro studies showed no appreciable binding of gadobenate ion to human serum proteins, in vivo studies have demonstrated a weak affinity binding of gadobenate to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. A small percentage of the administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Gadobenate ion has a rapid distribution half-life (reported as mean ± SD) of 0.084 ± 0.012 to 0.605 ± 0.072 hours. The mean elimination half-life ranged from 1.17 ± 0.26 to 2.02 ± 0.60 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total plasma clearance and renal clearance estimates of gadobenate ion were similar, ranging from 0.093 ± 0.010 to 0.133 ± 0.270 L/hr/kg and 0.082 ± 0.007 to 0.104 ± 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. In animal reproduction studies, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. There were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose. Because of the potential risks of gadolinium to the fetus, use gadobenate dimeglumine only if imaging is essential and cannot be delayed. Clinical consequences of overdosage with gadobenate dimeglumine have not been reported. Treatment of an overdosage should be directed toward support of vital functions and prompt institution of symptomatic therapy. In a Phase 1 clinical study, doses up to 0.4 mmol/kg were administered to patients. Gadobenate dimeglumine has been shown to be dialyzable. Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadobenate dimeglumine. The results for gadobenate dimeglumine were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats. Gadobenate dimeglumine had no effect on fertility and reproductive performance at IV doses of up to 2 mmol/kg/day (3 times the human dose on body surface basis) for 13 weeks in male rats and for 32 days in female rats. However, vacuolation in testes and abnormal spermatogenic cells were observed when gadobenate dimeglumine was intravenously administered to male rats at 3 mmol/kg/day (5 times the human dose on body surface basis) for 28 days. The effects were not reversible following 28-day recovery period. The effects were not reported in dog and monkey studies (at doses up to about 11 and 10 times the human dose on body surface basis for dogs (28 days dosing) and monkeys (14 days dosing), respectively). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Multihance •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gadobenic acid is a gadolinium-based contrast agent (GBCA) used with contrasted magnetic resonance imaging (MRI) to detect and visualize lesions and abnormal vascularity.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Gadobenic acid interact? Information: •Drug A: Buserelin •Drug B: Gadobenic acid •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Gadobenic acid. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Gadobenate dimeglumine is indicated for use in magnetic resonance imaging (MRI) of the central nervous system in adult and pediatric patients in order to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. It is also indicated for use in magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Unlike other paramagnetic contrast agents, gadobenate dimeglumine demonstrates weak and transient interactions with serum proteins that cause slowing in the molecular tumbling dynamics, resulting in strong increases in relaxivity in solutions containing serum proteins. The improved relaxation effect can contribute to increased contrast-to-noise ratio and lesion-to-brain ratio, which may improve visualization. Disruption of the blood-brain barrier or abnormal vascularity allows enhancement by gadobenate dimeglumine of lesions such as neoplasms, abscesses, and infarcts. Uptake of gadobenate dimeglumine into hepatocytes has been demonstrated. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The large magnetic moment produced by the paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue. In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At recommended doses, the effect is observed with the greatest sensitivity in the T1-weighted sequences. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Three single-dose intravenous studies were conducted in 32 healthy male subjects to assess the pharmacokinetics of gadobenate dimeglumine. The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg. Upon injection, the meglumine salt is completely dissociated from the gadobenate dimeglumine complex. Thus, the pharmacokinetics is based on the assay of gadobenate ion, the MRI contrast effective ion in gadobenate dimeglumine. Data for plasma concentration and area under the curve demonstrated linear dependence on the administered dose. The pharmacokinetics of gadobenate ion following intravenous administration can be best described using a two-compartment model. A population pharmacokinetic analysis incorporated data from 25 healthy subjects (14 males and 11 females) and 15 subjects undergoing MR imaging of the central nervous system (7 males and 8 females) between ages of 2 and 16 years. The subjects received a single intravenous dose of 0.1 mmol/kg of gadobenate dimeglumine. The geometric mean C max was 62.3 µg/mL (n=16) in children 2 to 5 years of age, and 64.2 µg/mL (n=24) in children older than 5 years. The geometric mean AUC 0-∞ was 77.9 μg⋅h/mL in children 2-5 years of age (n=16) and 82.6 μg⋅h/mL in children older than 5 years (n=24). The geometric mean half-life was 1.2 hours in children 2 to 5 years of age and 0.93 hours in children older than 5 years. There was no significant gender-related difference in the pharmacokinetic parameters in the pediatric patients. Pharmacokinetic simulations indicate similar AUC and Cmax values for gadobenate dimeglumine in pediatric subjects less than 2 years when compared to those reported for adults; no age-based dose adjustment is necessary for this pediatric population. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of the central compartment ranged from 0.074 ± 0.017 to 0.158 ± 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170 ± 0.016 to 0.282 ± 0.079 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Although in vitro studies showed no appreciable binding of gadobenate ion to human serum proteins, in vivo studies have demonstrated a weak affinity binding of gadobenate to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. A small percentage of the administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Gadobenate ion has a rapid distribution half-life (reported as mean ± SD) of 0.084 ± 0.012 to 0.605 ± 0.072 hours. The mean elimination half-life ranged from 1.17 ± 0.26 to 2.02 ± 0.60 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total plasma clearance and renal clearance estimates of gadobenate ion were similar, ranging from 0.093 ± 0.010 to 0.133 ± 0.270 L/hr/kg and 0.082 ± 0.007 to 0.104 ± 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. In animal reproduction studies, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. There were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose. Because of the potential risks of gadolinium to the fetus, use gadobenate dimeglumine only if imaging is essential and cannot be delayed. Clinical consequences of overdosage with gadobenate dimeglumine have not been reported. Treatment of an overdosage should be directed toward support of vital functions and prompt institution of symptomatic therapy. In a Phase 1 clinical study, doses up to 0.4 mmol/kg were administered to patients. Gadobenate dimeglumine has been shown to be dialyzable. Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadobenate dimeglumine. The results for gadobenate dimeglumine were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats. Gadobenate dimeglumine had no effect on fertility and reproductive performance at IV doses of up to 2 mmol/kg/day (3 times the human dose on body surface basis) for 13 weeks in male rats and for 32 days in female rats. However, vacuolation in testes and abnormal spermatogenic cells were observed when gadobenate dimeglumine was intravenously administered to male rats at 3 mmol/kg/day (5 times the human dose on body surface basis) for 28 days. The effects were not reversible following 28-day recovery period. The effects were not reported in dog and monkey studies (at doses up to about 11 and 10 times the human dose on body surface basis for dogs (28 days dosing) and monkeys (14 days dosing), respectively). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Multihance •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gadobenic acid is a gadolinium-based contrast agent (GBCA) used with contrasted magnetic resonance imaging (MRI) to detect and visualize lesions and abnormal vascularity. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Galantamine interact?

•Drug A: Buserelin •Drug B: Galantamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Galantamine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Galantamine is a competitive and reversible inhibitor of acetylcholinesterase that works to increase acetylcholine levels. Galantamine acts both centrally and peripherally to inhibit both muscle and brain acetylcholinesterase, thereby increasing cholinergic tone. Galantamine is also a positive allosteric modulator of neuronal nicotinic acetylcholine receptors. As dementia is a progressive neurodegenerative disease, galatamine has a negligible effect in altering the course of the underlying process of dementia and may exert its therapeutic effectiveness for a short period of time. However, galantamine promoted improvements in cognition, global function, activities of daily living, and behavioural symptoms in clinical studies of Alzheimer’s disease. Galantamine exhibited therapeutic efficacy in studies of vascular dementia and Alzheimer’s disease with cerebrovascular disease. In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome that was characterized by drowsiness, disorientation, and delirium. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients. Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galantamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft. Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galantamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Over a dose range of 8-32 mg/day, galantamine exhibits a dose-linear pharmacokinetic profile. The oral bioavailability of galantamine ranges from 90-100%. Following oral administration, the Tmax is about 1 hour. Following 10 hours of administration, the mean galantamine plasma concentrations were 82–97 µg/L for the 24 mg/day dose and 114–126 µg/L for the 32 mg/day dose. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean volume of distribution is 175 L. About 52.7% of galantamine is distributed to blood cells, the blood to plasma concentration ratio of galantamine is 1.2. Galantamine penetrates the blood–brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro study findings suggest that about 75% of the drug is metabolized by CYP2D6 and CYP3A4. CYP2D6 promotes O-demethylation of the drug to form O-desmethyl-galantamine and the CYP3A4-mediated pathway forms the galantamine-N-oxide. Important metabolic pathways also include N-demethylation, epimerization, and sulfate conjugation. Other metabolites include norgalantamine, O-desmethyl-galantamine, O-desmethyl-norgalantamine, epigalantamine and galantaminone, which do not retain clinically significant pharmacology activities. Galantamine can also undergo glucuronidation: in one oral radiolabeled drug study in poor and extensive CYP2D6 metabolizers, about 14-24% of the total radioactivity was identified as galantamine glucuronide 8 hours post-dose. O-demethylation by CYP2D6 becomes prominent in patients with who are extensive metabolizers of CYP2D6, but unchanged galatamine (39-77%) and its glucuronide metabolite (14-24%) predominated in the plasma of both poor and extensive metabolizers of CYP2D6 in a radiolabelled drug study. The total plasma clearance, or nonrenal clearnace, accounts for 20–25% of drug elimination. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal clearance accounts for about 20–25% of total plasma clearance of the drug in healthy individuals: the elimination of galantamine has been shown to be decreased in subjects with renal impairment. Following oral or intravenous administration, approximately 20% of the dose is excreted as unchanged in the urine within 24 h. In a radiolabelled drug study, about 95% and 5% of the total radioactivity was recovered in the urine and feces, respectively. Of the dose recovered in the urine, about 32% was in the unchanged parent compound, and 12% was in the glucuronide form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Galantamine has a terminal half-life of about 7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance is 65 mL/min and the total plasma clearance is about 300 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 of the active ingredient, galantamine hydrobromide, in rats is 75 mg/kg. Symptoms of overdose are expected to be similar to those of cholinomimetics, which involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. Effects of a cholinergic crisis include severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness or fasciculations may also occur, with respiratory muscle weakness having the potential to bring fatal results. In one patient who consumed an oral daily dose of 32 mg developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness. In one patient with a history of hallucinations who consumed a daily dose of 24 mg galantamine, hallucinations requiring hospitalization occurred. A patient who ingested 160 mg of galantamine from an oral solution developed sweating, vomiting, bradycardia, and near-syncope one hour following consumption. As in any case of overdose, general supportive measures should be initiated. Tertiary anticholinergics such as intravenous atropine may be used to reverse the cholinergic effects of galantamine. The recommended initial dose of atropine intravenously administered for galantamine overdose ranges from 0.5 to 1.0 mg. It is not known whether galantamine can be removed by dialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Razadyne •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Galantamina Galantamine Galanthamine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Galantamine is a cholinesterase inhibitor used to manage mild to moderate dementia associated with Alzheimer's Disease.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Galantamine interact? Information: •Drug A: Buserelin •Drug B: Galantamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Galantamine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Galantamine is a competitive and reversible inhibitor of acetylcholinesterase that works to increase acetylcholine levels. Galantamine acts both centrally and peripherally to inhibit both muscle and brain acetylcholinesterase, thereby increasing cholinergic tone. Galantamine is also a positive allosteric modulator of neuronal nicotinic acetylcholine receptors. As dementia is a progressive neurodegenerative disease, galatamine has a negligible effect in altering the course of the underlying process of dementia and may exert its therapeutic effectiveness for a short period of time. However, galantamine promoted improvements in cognition, global function, activities of daily living, and behavioural symptoms in clinical studies of Alzheimer’s disease. Galantamine exhibited therapeutic efficacy in studies of vascular dementia and Alzheimer’s disease with cerebrovascular disease. In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome that was characterized by drowsiness, disorientation, and delirium. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients. Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galantamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft. Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galantamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Over a dose range of 8-32 mg/day, galantamine exhibits a dose-linear pharmacokinetic profile. The oral bioavailability of galantamine ranges from 90-100%. Following oral administration, the Tmax is about 1 hour. Following 10 hours of administration, the mean galantamine plasma concentrations were 82–97 µg/L for the 24 mg/day dose and 114–126 µg/L for the 32 mg/day dose. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean volume of distribution is 175 L. About 52.7% of galantamine is distributed to blood cells, the blood to plasma concentration ratio of galantamine is 1.2. Galantamine penetrates the blood–brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro study findings suggest that about 75% of the drug is metabolized by CYP2D6 and CYP3A4. CYP2D6 promotes O-demethylation of the drug to form O-desmethyl-galantamine and the CYP3A4-mediated pathway forms the galantamine-N-oxide. Important metabolic pathways also include N-demethylation, epimerization, and sulfate conjugation. Other metabolites include norgalantamine, O-desmethyl-galantamine, O-desmethyl-norgalantamine, epigalantamine and galantaminone, which do not retain clinically significant pharmacology activities. Galantamine can also undergo glucuronidation: in one oral radiolabeled drug study in poor and extensive CYP2D6 metabolizers, about 14-24% of the total radioactivity was identified as galantamine glucuronide 8 hours post-dose. O-demethylation by CYP2D6 becomes prominent in patients with who are extensive metabolizers of CYP2D6, but unchanged galatamine (39-77%) and its glucuronide metabolite (14-24%) predominated in the plasma of both poor and extensive metabolizers of CYP2D6 in a radiolabelled drug study. The total plasma clearance, or nonrenal clearnace, accounts for 20–25% of drug elimination. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal clearance accounts for about 20–25% of total plasma clearance of the drug in healthy individuals: the elimination of galantamine has been shown to be decreased in subjects with renal impairment. Following oral or intravenous administration, approximately 20% of the dose is excreted as unchanged in the urine within 24 h. In a radiolabelled drug study, about 95% and 5% of the total radioactivity was recovered in the urine and feces, respectively. Of the dose recovered in the urine, about 32% was in the unchanged parent compound, and 12% was in the glucuronide form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Galantamine has a terminal half-life of about 7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance is 65 mL/min and the total plasma clearance is about 300 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 of the active ingredient, galantamine hydrobromide, in rats is 75 mg/kg. Symptoms of overdose are expected to be similar to those of cholinomimetics, which involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. Effects of a cholinergic crisis include severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness or fasciculations may also occur, with respiratory muscle weakness having the potential to bring fatal results. In one patient who consumed an oral daily dose of 32 mg developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness. In one patient with a history of hallucinations who consumed a daily dose of 24 mg galantamine, hallucinations requiring hospitalization occurred. A patient who ingested 160 mg of galantamine from an oral solution developed sweating, vomiting, bradycardia, and near-syncope one hour following consumption. As in any case of overdose, general supportive measures should be initiated. Tertiary anticholinergics such as intravenous atropine may be used to reverse the cholinergic effects of galantamine. The recommended initial dose of atropine intravenously administered for galantamine overdose ranges from 0.5 to 1.0 mg. It is not known whether galantamine can be removed by dialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Razadyne •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Galantamina Galantamine Galanthamine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Galantamine is a cholinesterase inhibitor used to manage mild to moderate dementia associated with Alzheimer's Disease. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Gatifloxacin interact?

•Drug A: Buserelin •Drug B: Gatifloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Gatifloxacin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of bronchitis, sinusitis, community-acquired pneumonia, and skin infections (abscesses, wounds) caused by S. pneumoniae, H. influenzae, S. aureus, M. pneumoniae, C. pneumoniae, L. pneumophila, S. pyogenes •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent for oral or intravenous administration. is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Gatifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The bactericidal action of Gatifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed from the gastrointestinal tract after oral administration with absolute bioavailability of gatifloxacin is 96% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 20% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gatifloxacin undergoes limited biotransformation in humans with less than 1% of the dose excreted in the urine as ethylenediamine and methylethylenediamine metabolites •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7-14 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zymar, Zymaxid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gatifloxacin Gatifloxacine Gatifloxacino Gatifloxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gatifloxacin is a fourth generation fluoroquinolone used to treat a wide variety of infections in the body.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Gatifloxacin interact? Information: •Drug A: Buserelin •Drug B: Gatifloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Gatifloxacin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of bronchitis, sinusitis, community-acquired pneumonia, and skin infections (abscesses, wounds) caused by S. pneumoniae, H. influenzae, S. aureus, M. pneumoniae, C. pneumoniae, L. pneumophila, S. pyogenes •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent for oral or intravenous administration. is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Gatifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The bactericidal action of Gatifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed from the gastrointestinal tract after oral administration with absolute bioavailability of gatifloxacin is 96% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 20% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gatifloxacin undergoes limited biotransformation in humans with less than 1% of the dose excreted in the urine as ethylenediamine and methylethylenediamine metabolites •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7-14 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zymar, Zymaxid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gatifloxacin Gatifloxacine Gatifloxacino Gatifloxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gatifloxacin is a fourth generation fluoroquinolone used to treat a wide variety of infections in the body. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Gemifloxacin interact?

•Drug A: Buserelin •Drug B: Gemifloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Gemifloxacin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of bacterial infection caused by susceptible strains such as S. pneumoniae, H. influenzae, H. parainfluenzae, or M. catarrhalis, S. pneumoniae (including multi-drug resistant strains [MDRSP]), M. pneumoniae, C. pneumoniae, or K. pneumoniae. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Gemifloxacin is a quinolone/fluoroquinolone antibiotic. Gemifloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Gemifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The bactericidal action of gemifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. The absolute bioavailability averages approximately 71%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 1.66 to 12.12 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 60-70% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gemifloxacin is metabolized to a limited extent by the liver. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Gemifloxacin and its metabolites are excreted via dual routes of excretion.Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7 (± 2) hours •Clearance (Drug A): No clearance available •Clearance (Drug B): renal cl=11.6+/- 3.9 L/hr [Healthy subjects receiving repeat doses of 320 mg orally] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Factive •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gemifloxacin is a quinolone antibacterial agent used for the treatment of acute bacterial exacerbation of chronic bronchitis and mild to moderate community-acquired pneumonia caused by susceptible bacteria.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Gemifloxacin interact? Information: •Drug A: Buserelin •Drug B: Gemifloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Gemifloxacin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of bacterial infection caused by susceptible strains such as S. pneumoniae, H. influenzae, H. parainfluenzae, or M. catarrhalis, S. pneumoniae (including multi-drug resistant strains [MDRSP]), M. pneumoniae, C. pneumoniae, or K. pneumoniae. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Gemifloxacin is a quinolone/fluoroquinolone antibiotic. Gemifloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Gemifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The bactericidal action of gemifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. The absolute bioavailability averages approximately 71%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 1.66 to 12.12 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 60-70% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gemifloxacin is metabolized to a limited extent by the liver. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Gemifloxacin and its metabolites are excreted via dual routes of excretion.Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7 (± 2) hours •Clearance (Drug A): No clearance available •Clearance (Drug B): renal cl=11.6+/- 3.9 L/hr [Healthy subjects receiving repeat doses of 320 mg orally] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Factive •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gemifloxacin is a quinolone antibacterial agent used for the treatment of acute bacterial exacerbation of chronic bronchitis and mild to moderate community-acquired pneumonia caused by susceptible bacteria. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Gepirone interact?

•Drug A: Buserelin •Drug B: Gepirone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Gepirone is combined with Buserelin. •Extended Description: Gepirone was observed to cause QT prolongation, although the exact mechanism of action is unknown. Therefore, the concomitant use of gepirone with another QTc prolonging agent can have an additive effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3’-OH-gepirone and 1- PP. Gepirone and its 3’-OH metabolite bind to 5HT 1A receptors (K i = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to α 2 receptors (K i = 42 nM). In a thorough QT study, the largest mean increase in baseline- and placebo-corrected QTc interval with administration of 100 mg per day immediate-release formulation of gepirone was 18.4 msec (upper 90% confidence interval [CI] = 22.7 ms) on Day 1 and 16.1 msec (upper 90% CI = 20.7 ms) on Day 7. The exposure in this study was 2-fold the exposure of the maximum recommended dose. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT 1a receptors. Particularly, gepirone •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetics of gepirone are linear and dose-proportional from 18.2 mg to 72.6 mg. Steady-state plasma concentrations are typically achieved within two to four days of daily dosing. The absolute bioavailability is 14% to 17%. The maximal plasma gepirone concentration (C max ) after dosing is reached within 6 hours post-dose (T max ). After a high-fat meal, T max is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (C max ) of gepirone and, to a lesser extent, on the total exposure (AUC 0-t last, AUC 0-∞ ) to gepirone. The magnitude of the food effect was dependent of the fat content of the meal. The systemic exposure of gepirone and major metabolites was consistently higher under fed conditions as compared to the fasted state. Gepirone C max after intake of a low-fat (~ 200 calories) breakfast was 27% higher, after medium-fat (~500 calories) breakfast 55% higher, and after a high-fat (~ 850 calories) breakfast 62% higher as compared to the fasted state. The AUC after intake of a low-fat breakfast was about 14% higher, after a medium-fat breakfast 22% higher, and after a high-fat breakfast 32 to 37% higher as compared to the fasted state. The effect of varying amounts of fat on C max and AUC of the major metabolites 3-OH-gepirone and 1PP were similar to that found for gepirone. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of gepirone is approximately 94.5L. •Protein binding (Drug A): 15% •Protein binding (Drug B): The in vitro plasma protein binding in humans is 72% and is not concentration-dependent. The in vitro plasma protein binding for metabolite 3’-OH gepirone is 59% and 42% for 1-PP. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gepirone is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound. CYP3A4 is the primary enzyme catalyzing the metabolism of EXXUA to its major pharmacologically active metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose of [ C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of gepirone. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life is approximately 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): After the administration of 80 mg of gepirone, the apparent clearance of gepirone and its 2 metabolites, 1-PP and 3’-OH-gepirone, was calculated to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61.7 L/h respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In embryo-fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg) or pregnant rabbits (50, 100, and 200 mg/kg) during the period of organogenesis resulted in decreased embryofetal growth, body weights, and lengths, with accompanying skeletal variations at mid and high doses; the mid doses are 18 and 24 times the maximum recommended human dose (MRHD) on a mg/m basis in rats and rabbits, respectively. No malformations were seen in these studies. The developmental no observed adverse effect level (NOAEL) was 9 and 12 times the MRHD on a mg/m2 basis in rats and rabbits, respectively. When pregnant rats were treated with gepirone (10, 20, and 40 mg/kg) from late gestation through weaning, decreased birth weights were seen at mid and high doses; the mid-dose is twice the MRHD. Increased offspring mortality during the first 4 days after birth and persistent reduction in body weight were observed at all doses; the lowest dose is approximately equal to the MRHD on a mg/m basis. The no-effect dose for fetal effects was not determined in this study. When gepirone was administered orally to male and female rats prior to and throughout mating, gestation, and lactation at doses of 5, 27, 64, and 150 mg/kg/day, increased stillbirths were seen at ≥64 mg/kg. Early postnatal mortality was increased at 150 mg/kg (18 times the MRHD on a mg/m basis). The NOAEL (27 mg/kg) for stillbirths was associated with a maternal dose 3 times the MRHD on a mg/m basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m2 basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m basis) and above. Pup weights were decreased at birth, throughout lactation and weaning, and until at least 14 weeks of age, with delays of some developmental landmarks, at 64 mg/kg and above. The NOAEL for growth and development (5 mg/kg) was associated with a maternal dose below the MRHD on a mg/m2 basis. In the pediatric trial patients, there was a higher occurrence of vomiting in pediatric patients (13%) compared to adults (6.6%). Antidepressants, such as gepirone, increase the risk of suicidal thoughts and behaviors in pediatric patients. In clinical studies, cases of acute ingestions of up to 454 mg (6.25 times the maximum recommended dose) of gepirone alone or in combination with other drugs, were reported. Signs and symptoms reported with an overdose of gepirone at doses up to 454 mg included vomiting and transient incomplete bundle branch block; an unknown dose of gepirone produced an altered level of consciousness and a 60-second convulsion. No specific antidotes for gepirone are known. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. No evidence of carcinogenic potential was observed in lifetime carcinogenicity studies performed in rats and mice at doses up to 43.6 and 317.8 mg/kg/day, respectively. These doses are approximately 6 and 18 times the MRHD, respectively, on a mg/m basis. Gepirone showed no mutagenicity in three different in vitro genotoxicity assays (bacterial gene mutation, mammalian gene mutation, or DNA repair). No clastogenicity was observed in a rat micronucleus assay. When gepirone was administered orally to male and female rats prior to and throughout mating at daily doses of 5, 27, 64, and 150 mg/kg, the latency to mating was increased at doses of 64 mg/kg (8 times the MRHD on a mg/m basis) and above. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Exxua •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gepirone is a serotonin receptor agonist used to treat major depressive disorder in adults

Gepirone was observed to cause QT prolongation, although the exact mechanism of action is unknown. Therefore, the concomitant use of gepirone with another QTc prolonging agent can have an additive effect. The severity of the interaction is moderate.

Question: Does Buserelin and Gepirone interact? Information: •Drug A: Buserelin •Drug B: Gepirone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Gepirone is combined with Buserelin. •Extended Description: Gepirone was observed to cause QT prolongation, although the exact mechanism of action is unknown. Therefore, the concomitant use of gepirone with another QTc prolonging agent can have an additive effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3’-OH-gepirone and 1- PP. Gepirone and its 3’-OH metabolite bind to 5HT 1A receptors (K i = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to α 2 receptors (K i = 42 nM). In a thorough QT study, the largest mean increase in baseline- and placebo-corrected QTc interval with administration of 100 mg per day immediate-release formulation of gepirone was 18.4 msec (upper 90% confidence interval [CI] = 22.7 ms) on Day 1 and 16.1 msec (upper 90% CI = 20.7 ms) on Day 7. The exposure in this study was 2-fold the exposure of the maximum recommended dose. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT 1a receptors. Particularly, gepirone •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetics of gepirone are linear and dose-proportional from 18.2 mg to 72.6 mg. Steady-state plasma concentrations are typically achieved within two to four days of daily dosing. The absolute bioavailability is 14% to 17%. The maximal plasma gepirone concentration (C max ) after dosing is reached within 6 hours post-dose (T max ). After a high-fat meal, T max is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (C max ) of gepirone and, to a lesser extent, on the total exposure (AUC 0-t last, AUC 0-∞ ) to gepirone. The magnitude of the food effect was dependent of the fat content of the meal. The systemic exposure of gepirone and major metabolites was consistently higher under fed conditions as compared to the fasted state. Gepirone C max after intake of a low-fat (~ 200 calories) breakfast was 27% higher, after medium-fat (~500 calories) breakfast 55% higher, and after a high-fat (~ 850 calories) breakfast 62% higher as compared to the fasted state. The AUC after intake of a low-fat breakfast was about 14% higher, after a medium-fat breakfast 22% higher, and after a high-fat breakfast 32 to 37% higher as compared to the fasted state. The effect of varying amounts of fat on C max and AUC of the major metabolites 3-OH-gepirone and 1PP were similar to that found for gepirone. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of gepirone is approximately 94.5L. •Protein binding (Drug A): 15% •Protein binding (Drug B): The in vitro plasma protein binding in humans is 72% and is not concentration-dependent. The in vitro plasma protein binding for metabolite 3’-OH gepirone is 59% and 42% for 1-PP. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gepirone is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound. CYP3A4 is the primary enzyme catalyzing the metabolism of EXXUA to its major pharmacologically active metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose of [ C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of gepirone. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life is approximately 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): After the administration of 80 mg of gepirone, the apparent clearance of gepirone and its 2 metabolites, 1-PP and 3’-OH-gepirone, was calculated to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61.7 L/h respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In embryo-fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg) or pregnant rabbits (50, 100, and 200 mg/kg) during the period of organogenesis resulted in decreased embryofetal growth, body weights, and lengths, with accompanying skeletal variations at mid and high doses; the mid doses are 18 and 24 times the maximum recommended human dose (MRHD) on a mg/m basis in rats and rabbits, respectively. No malformations were seen in these studies. The developmental no observed adverse effect level (NOAEL) was 9 and 12 times the MRHD on a mg/m2 basis in rats and rabbits, respectively. When pregnant rats were treated with gepirone (10, 20, and 40 mg/kg) from late gestation through weaning, decreased birth weights were seen at mid and high doses; the mid-dose is twice the MRHD. Increased offspring mortality during the first 4 days after birth and persistent reduction in body weight were observed at all doses; the lowest dose is approximately equal to the MRHD on a mg/m basis. The no-effect dose for fetal effects was not determined in this study. When gepirone was administered orally to male and female rats prior to and throughout mating, gestation, and lactation at doses of 5, 27, 64, and 150 mg/kg/day, increased stillbirths were seen at ≥64 mg/kg. Early postnatal mortality was increased at 150 mg/kg (18 times the MRHD on a mg/m basis). The NOAEL (27 mg/kg) for stillbirths was associated with a maternal dose 3 times the MRHD on a mg/m basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m2 basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m basis) and above. Pup weights were decreased at birth, throughout lactation and weaning, and until at least 14 weeks of age, with delays of some developmental landmarks, at 64 mg/kg and above. The NOAEL for growth and development (5 mg/kg) was associated with a maternal dose below the MRHD on a mg/m2 basis. In the pediatric trial patients, there was a higher occurrence of vomiting in pediatric patients (13%) compared to adults (6.6%). Antidepressants, such as gepirone, increase the risk of suicidal thoughts and behaviors in pediatric patients. In clinical studies, cases of acute ingestions of up to 454 mg (6.25 times the maximum recommended dose) of gepirone alone or in combination with other drugs, were reported. Signs and symptoms reported with an overdose of gepirone at doses up to 454 mg included vomiting and transient incomplete bundle branch block; an unknown dose of gepirone produced an altered level of consciousness and a 60-second convulsion. No specific antidotes for gepirone are known. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. No evidence of carcinogenic potential was observed in lifetime carcinogenicity studies performed in rats and mice at doses up to 43.6 and 317.8 mg/kg/day, respectively. These doses are approximately 6 and 18 times the MRHD, respectively, on a mg/m basis. Gepirone showed no mutagenicity in three different in vitro genotoxicity assays (bacterial gene mutation, mammalian gene mutation, or DNA repair). No clastogenicity was observed in a rat micronucleus assay. When gepirone was administered orally to male and female rats prior to and throughout mating at daily doses of 5, 27, 64, and 150 mg/kg, the latency to mating was increased at doses of 64 mg/kg (8 times the MRHD on a mg/m basis) and above. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Exxua •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gepirone is a serotonin receptor agonist used to treat major depressive disorder in adults Output: Gepirone was observed to cause QT prolongation, although the exact mechanism of action is unknown. Therefore, the concomitant use of gepirone with another QTc prolonging agent can have an additive effect. The severity of the interaction is moderate.

Does Buserelin and Gilteritinib interact?

•Drug A: Buserelin •Drug B: Gilteritinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Gilteritinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay. Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result in vivo was the localization in high levels in xenografted tumors which indicated high selectivity. In phase 1/2 clinical trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks. In phase III clinical trials, gilteritinib reported a complete remission or complete remission with partial hematologic recovery in 21% of the patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT. The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation. In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The reported median half-life of gilteritinib was of approximate 45-159 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The estimated clearance of gilteritinib is 14.85 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Gilteritinib is not reported to be mutagenic in bacterial mutagenesis assays nor clastogenic in aberration test assays in Chinese hamster lung cells. However, it resulted positive for the induction of micronuclei in mouse bone marrow and for the degeneration and necrosis of germ cells and spermatid giant cell formation in testis as well as single cell necrosis of the epididymal duct epithelia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xospata •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gilteritinib is an AXL receptor tyrosine kinase inhibitor used to treat relapsed or refractory acute myeloid leukemia.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Gilteritinib interact? Information: •Drug A: Buserelin •Drug B: Gilteritinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Gilteritinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay. Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result in vivo was the localization in high levels in xenografted tumors which indicated high selectivity. In phase 1/2 clinical trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks. In phase III clinical trials, gilteritinib reported a complete remission or complete remission with partial hematologic recovery in 21% of the patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT. The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation. In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The reported median half-life of gilteritinib was of approximate 45-159 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The estimated clearance of gilteritinib is 14.85 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Gilteritinib is not reported to be mutagenic in bacterial mutagenesis assays nor clastogenic in aberration test assays in Chinese hamster lung cells. However, it resulted positive for the induction of micronuclei in mouse bone marrow and for the degeneration and necrosis of germ cells and spermatid giant cell formation in testis as well as single cell necrosis of the epididymal duct epithelia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xospata •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gilteritinib is an AXL receptor tyrosine kinase inhibitor used to treat relapsed or refractory acute myeloid leukemia. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Givinostat interact?

•Drug A: Buserelin •Drug B: Givinostat •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Givinostat. •Extended Description: Givinostat can cause QTc interval prolongation. Concomitant use of givinostat with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTcvinterval prolongation, including Torsade de pointes, other serious arrhythmias, and sudden death. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Givinostat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients ≥6 years of age. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The efficacy givinostat was demonstrated in a randomized, double-blind, placebo-controlled trial wherein muscle function was evaluated by measuring the change from baseline to 18 months in the time taken to ascend four stairs. Patients treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo - the mean change was 1.25 seconds for patients receiving givinostat compared to 3.03 seconds for patients receiving placebo. Givinostat causes QTc interval prolongation and should be used with caution in patients with underlying cardiac disease or in patients who are taking concomitant medications that may prolong the QT interval. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Givinostat is a histone deacetylase inhibitor. The precise mechanism by which givinostat exerts its therapeutic effects in patients with DMD is unknown. Histone deacetylases (HDACs), as the name implies, regulate the deacetylation of various proteins. The acetylation and deacetylation of histone proteins causes an increase or decrease in gene expression, respectively, with the latter function governed by HDACs. The balance between levels of histone acetylation and deacetylation plays a key role in the modulation of gene transcription and governs numerous developmental processes, being involved in the regulation of various genes associated with signal transduction, cell growth, and cell death, as well as diseases like cancers. HDACs can deacetylate non-histone proteins, such as p53, thereby also regulating their activity. Several HDAC isoforms have been implicated in skeletal muscle remodeling - under both physiological and pathological conditions - which serve to regulate fiber type specification, muscle fiber size and innervation, metabolic fuel switching, muscle development, insulin sensitivity, and exercise capacity. This gave rise to interest in HDACs as a potential target in the treatment of muscular dystrophies, including Duchenne Muscular Dystrophy (DMD). Consistently, HDAC expression and activity have been found altered in muscular dystrophies, suggesting a role for these enzymes in the progression of the disease. The inhibition of these enzymes by HDAC inhibitors such as givinostat contributes to the preservation of muscle force and morphology. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absolute bioavailability of givinostat has not been determined. The T max of givinostat occurs approximately 2-3 hours following oral administration, and steady-state is achieved within 5 to 7 days with twice daily dosing. Systemic exposure is proportional to the administered dose across the therapeutic dose range. Administration with a high-fat meal resulted in a 40% increase in AUC, a 23% increase in C max, and a delay in T max of 2-3 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): According to population pharmacokinetic modeling, the estimated apparent volume of distribution of the central compartment is 160 L. The estimated apparent volume of distribution of the peripheral compartment is 483 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Givinostat is highly (~96%) protein bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Givinostat is extensively metabolized to several metabolites, four of which have been characterized: ITF2374, ITF2375, ITF2440, and ITF2563. These metabolites do not contribute to the efficacy of givinostat. The enzymes responsible for the metabolism of givinostat are unclear; its metabolism is not mediated by CYP450 or UGT enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urinary excretion of givinostat is minimal (<3%). The elimination of givinostat is likely driven by metabolism followed by renal and biliary excretion of the resulting metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The apparent plasma elimination half-life of givinostat is approximately 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): According to population pharmacokinetic modeling, the estimated apparent oral clearance of givinostat is 121 L/h. The estimated compartmental clearance of givinostat is 33.8 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There are no data available regarding overdosage with givinostat. In healthy subjects administered a dose of 265.8 mg (approximately 5-fold the 53.2 mg dose recommended for DMD patients weighing 60 kg or more), an increase in QTc interval 5 hours post-administration was observed, the largest mean increase being 13.6 ms. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Givinostat is a histone deacetylase inhibitor indicated for the treatment of Duchenne Muscular Dystrophy (DMD).

Givinostat can cause QTc interval prolongation. Concomitant use of givinostat with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTcvinterval prolongation, including Torsade de pointes, other serious arrhythmias, and sudden death. The severity of the interaction is moderate.

Question: Does Buserelin and Givinostat interact? Information: •Drug A: Buserelin •Drug B: Givinostat •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Givinostat. •Extended Description: Givinostat can cause QTc interval prolongation. Concomitant use of givinostat with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTcvinterval prolongation, including Torsade de pointes, other serious arrhythmias, and sudden death. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Givinostat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients ≥6 years of age. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The efficacy givinostat was demonstrated in a randomized, double-blind, placebo-controlled trial wherein muscle function was evaluated by measuring the change from baseline to 18 months in the time taken to ascend four stairs. Patients treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo - the mean change was 1.25 seconds for patients receiving givinostat compared to 3.03 seconds for patients receiving placebo. Givinostat causes QTc interval prolongation and should be used with caution in patients with underlying cardiac disease or in patients who are taking concomitant medications that may prolong the QT interval. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Givinostat is a histone deacetylase inhibitor. The precise mechanism by which givinostat exerts its therapeutic effects in patients with DMD is unknown. Histone deacetylases (HDACs), as the name implies, regulate the deacetylation of various proteins. The acetylation and deacetylation of histone proteins causes an increase or decrease in gene expression, respectively, with the latter function governed by HDACs. The balance between levels of histone acetylation and deacetylation plays a key role in the modulation of gene transcription and governs numerous developmental processes, being involved in the regulation of various genes associated with signal transduction, cell growth, and cell death, as well as diseases like cancers. HDACs can deacetylate non-histone proteins, such as p53, thereby also regulating their activity. Several HDAC isoforms have been implicated in skeletal muscle remodeling - under both physiological and pathological conditions - which serve to regulate fiber type specification, muscle fiber size and innervation, metabolic fuel switching, muscle development, insulin sensitivity, and exercise capacity. This gave rise to interest in HDACs as a potential target in the treatment of muscular dystrophies, including Duchenne Muscular Dystrophy (DMD). Consistently, HDAC expression and activity have been found altered in muscular dystrophies, suggesting a role for these enzymes in the progression of the disease. The inhibition of these enzymes by HDAC inhibitors such as givinostat contributes to the preservation of muscle force and morphology. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absolute bioavailability of givinostat has not been determined. The T max of givinostat occurs approximately 2-3 hours following oral administration, and steady-state is achieved within 5 to 7 days with twice daily dosing. Systemic exposure is proportional to the administered dose across the therapeutic dose range. Administration with a high-fat meal resulted in a 40% increase in AUC, a 23% increase in C max, and a delay in T max of 2-3 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): According to population pharmacokinetic modeling, the estimated apparent volume of distribution of the central compartment is 160 L. The estimated apparent volume of distribution of the peripheral compartment is 483 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Givinostat is highly (~96%) protein bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Givinostat is extensively metabolized to several metabolites, four of which have been characterized: ITF2374, ITF2375, ITF2440, and ITF2563. These metabolites do not contribute to the efficacy of givinostat. The enzymes responsible for the metabolism of givinostat are unclear; its metabolism is not mediated by CYP450 or UGT enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urinary excretion of givinostat is minimal (<3%). The elimination of givinostat is likely driven by metabolism followed by renal and biliary excretion of the resulting metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The apparent plasma elimination half-life of givinostat is approximately 6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): According to population pharmacokinetic modeling, the estimated apparent oral clearance of givinostat is 121 L/h. The estimated compartmental clearance of givinostat is 33.8 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There are no data available regarding overdosage with givinostat. In healthy subjects administered a dose of 265.8 mg (approximately 5-fold the 53.2 mg dose recommended for DMD patients weighing 60 kg or more), an increase in QTc interval 5 hours post-administration was observed, the largest mean increase being 13.6 ms. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Givinostat is a histone deacetylase inhibitor indicated for the treatment of Duchenne Muscular Dystrophy (DMD). Output: Givinostat can cause QTc interval prolongation. Concomitant use of givinostat with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTcvinterval prolongation, including Torsade de pointes, other serious arrhythmias, and sudden death. The severity of the interaction is moderate.

Does Buserelin and Glasdegib interact?

•Drug A: Buserelin •Drug B: Glasdegib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Glasdegib. •Extended Description: QTc prolongation is a known side effect of glasdegib.1 In a clinical trial, 5% of patients treated with 100 mg of glasdegib in combination with low-dose cytarabine were reported to have a QTc interval greater than 500 ms. Therefore, the concomitant use of glasdegib with another QTc prolonging agent can further increase the risk of QTc prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Glasdegib reported volume of distribution in a dose of 50 mg is 225 L. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. •Protein binding (Drug A): 15% •Protein binding (Drug B): Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The reported half-life of glasdegib is of 17.4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been performed with glasdegib. Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay. Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6 times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose-limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Daurismo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glasdegib is a sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy.

QTc prolongation is a known side effect of glasdegib.1 In a clinical trial, 5% of patients treated with 100 mg of glasdegib in combination with low-dose cytarabine were reported to have a QTc interval greater than 500 ms. Therefore, the concomitant use of glasdegib with another QTc prolonging agent can further increase the risk of QTc prolongation. The severity of the interaction is moderate.

Question: Does Buserelin and Glasdegib interact? Information: •Drug A: Buserelin •Drug B: Glasdegib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Glasdegib. •Extended Description: QTc prolongation is a known side effect of glasdegib.1 In a clinical trial, 5% of patients treated with 100 mg of glasdegib in combination with low-dose cytarabine were reported to have a QTc interval greater than 500 ms. Therefore, the concomitant use of glasdegib with another QTc prolonging agent can further increase the risk of QTc prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Glasdegib reported volume of distribution in a dose of 50 mg is 225 L. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. •Protein binding (Drug A): 15% •Protein binding (Drug B): Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The reported half-life of glasdegib is of 17.4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been performed with glasdegib. Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay. Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6 times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose-limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Daurismo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glasdegib is a sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy. Output: QTc prolongation is a known side effect of glasdegib.1 In a clinical trial, 5% of patients treated with 100 mg of glasdegib in combination with low-dose cytarabine were reported to have a QTc interval greater than 500 ms. Therefore, the concomitant use of glasdegib with another QTc prolonging agent can further increase the risk of QTc prolongation. The severity of the interaction is moderate.

Does Buserelin and Gliclazide interact?

•Drug A: Buserelin •Drug B: Gliclazide •Severity: MODERATE •Description: The therapeutic efficacy of Gliclazide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Based on the pharmacological properties, gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 94%, highly bound to plasma proteins •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10.4 hours. Duration of action is 10-24 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy, drowsiness, headache and sweating. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diamicron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gliclazida Gliclazide Gliclazidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gliclazide is a sulfonylurea used to treat hyperglycemia in patients with type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Gliclazide interact? Information: •Drug A: Buserelin •Drug B: Gliclazide •Severity: MODERATE •Description: The therapeutic efficacy of Gliclazide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Based on the pharmacological properties, gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 94%, highly bound to plasma proteins •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10.4 hours. Duration of action is 10-24 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy, drowsiness, headache and sweating. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diamicron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gliclazida Gliclazide Gliclazidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gliclazide is a sulfonylurea used to treat hyperglycemia in patients with type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Glimepiride interact?

•Drug A: Buserelin •Drug B: Glimepiride •Severity: MODERATE •Description: The therapeutic efficacy of Glimepiride can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels. A multi-center, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone. In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo. In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period. The 4- and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg). •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding of glimepiride is greater than 99.5%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours. However, whether the glucose-lowering effect of M1 is clinically significant is not clear. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses. •Clearance (Drug A): No clearance available •Clearance (Drug B): A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 value in rats is > 10000 mg/kg. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg. Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery. In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Duetact, Tandemact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glimepiride is a sulfonylurea drug used to treat type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Glimepiride interact? Information: •Drug A: Buserelin •Drug B: Glimepiride •Severity: MODERATE •Description: The therapeutic efficacy of Glimepiride can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels. A multi-center, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone. In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo. In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period. The 4- and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg). •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding of glimepiride is greater than 99.5%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours. However, whether the glucose-lowering effect of M1 is clinically significant is not clear. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses. •Clearance (Drug A): No clearance available •Clearance (Drug B): A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 value in rats is > 10000 mg/kg. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg. Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery. In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Duetact, Tandemact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glimepiride is a sulfonylurea drug used to treat type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Glipizide interact?

•Drug A: Buserelin •Drug B: Glipizide •Severity: MODERATE •Description: The therapeutic efficacy of Glipizide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Glipizide is a blood glucose-lowering agent. The initial onset of blood glucose-lowering effect occurs around 30 minutes post-administration with the duration of action lasting for about 12 to 24 hours. While the chronic use of glipizide does not result in elevations in the fasting insulin levels over time, the postprandial insulin response, or insulin response to a meal, is observed to be enhanced, even after 6 months of treatment. The main therapeutic actions of glipizide primarily occur at the pancreas where the insulin release is stimulated, but glipizide also mediates some extrapancreatic effects, such as the promotion of insulin signaling effects on the muscles, fat, or liver cells. Due to its action on the endogenous cells, sulfonylureas including glipizide is associated with a risk for developing hypoglycemia and weight gain in patients receiving the drug. Chronic administration of glipizide may result in down-regulation of the sulfonylurea receptors on pancreatic beta cells, which are molecular targets of the drug, leading to a reduced effect on insulin secretion. Like other sulfonylureas, glipizide may work on pancreatic delta (δ) cells and alpha (α) cells to stimulate the secretion of somatostatin and suppress the secretion of glucagon, which are peptide hormones that regulate neuroendocrine and metabolic pathways. Other than its primary action on the pancreas, glipizide also exerts other biological actions outside of the pancreas, or "extrapancreatic effects", which is similar to other members of the sulfonylurea drug class. Glipizide may enhance the glucose uptake into the skeletal muscles and potentiate the action of insulin in the liver. Other effects include inhibited lipolysis in the liver and adipose tissue, inhibited hepatic glucose output, and increased uptake and oxidation of glucose. It has also been demonstrated by several studies that the chronic therapeutic use of sulfonylureas may result in an increase in insulin receptors expressed on monocytes, adipocytes, and erythrocytes. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence worldwide. Characterized by higher-than-normal levels of blood glucose, T2DM is a complex disorder that arises from the interaction between genetic, environmental and behavioral risk factors. Insulin is a peptide hormone that plays a critical role in regulating blood glucose levels. In response to high blood glucose levels, insulin promotes the uptake of glucose into the liver, muscle cells, and fat cells for storage. Although there are multiple events occurring that lead to the pathophysiology of T2DM, the disorder mainly involves insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual failure of beta cells of pancreatic islets that normally produce insulin. Early management with lifestyle intervention, such as controlled diet and exercise, is critical in reducing the risk of long-term secondary complications, such as cardiovascular mortality. Glipizide, like other sulfonylurea drugs, is an insulin secretagogue, which works by stimulating the insulin release from the pancreatic beta cells thereby increasing the plasma concentrations of insulin. Thus, the main therapeutic action of the drug depends on the functional beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor expressed on the pancreatic beta-cell plasma membrane, leading to the closure of the ATP-sensitive potassium channel and reduced potassium conductance. This results in depolarization of the pancreatic beta cell and opening of the voltage-sensitive calcium channels, promoting calcium ion influx. Increased intracellular concentrations of calcium ions in beta cells stimulates the secretion, or exocytosis, of insulin granules from the cells. Apart from this main mechanism of action, the blood-glucose-lowering effect of glipizide involves increased peripheral glucose utilization via stimulating hepatic gluconeogenesis and by increasing the number and sensitivity of insulin receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. The absolute bioavailability of glipizide in patients with type 2 diabetes receiving a single oral dose was 100%. The maximum plasma concentrations are expected to be reached within 6 to 12 hours following initial dosing. The steady-state plasma concentrations of glipizide from extended-release oral formulations are maintained over the 24-hour dosing interval. In healthy volunteers, the absorption of glipizide was delayed by the presence of food but the total absorption was unaffected. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean volume of distribution was approximately 10 L following administration of single intravenous doses in patients with type 2 diabetes mellitus. In mice and rat studies, the presence of the drug and its metabolites was none to minimal in the fetus of pregnant female animals. Other sulfonylurea drugs were shown to cross the placenta and enter breast milk thus the potential risk of glipizide in fetus or infants cannot be excluded. •Protein binding (Drug A): 15% •Protein binding (Drug B): Glipizide is about 98-99% bound to serum proteins, with albumin being the main plasma protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Glipizide is subject to hepatic metabolism, in which its major metabolites are formed from aromatic hydroxylation. These major metabolites are glipizide are reported to be pharmacologically inactive. In contrast, an acetylaminoethyl benzine derivative is formed as a minor metabolite which accounts for less than 2% of the initial dose and is reported to have one-tenth to one-third as much hypoglycemic activity as the parent compound. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Glipizide is mainly eliminated by hepatic biotransformation, where less than 10% of the initial dose of the drug can be detected in the urine and feces as unchanged glipizide. About 80% of the metabolites of glipizide is excreted in the urine while 10% is excreted in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total body clearance of glipizide was approximately 3 L/hr following administration of single intravenous doses in patients with type 2 diabetes mellitus. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In rats, the oral LD 50 is reported to be greater than 4000 mg/kg and the intraperitoneal LD 50 is 1200 mg/kg. The lowest published toxic dose (TDLo) via oral route in child was 379 μg/kg. Symptoms of overdose in sulfonylureas, including glipizide, may be related to severe hypoglycemia and may include coma, seizure, or other neurological impairment. These are symptoms of severe hypoglycemia and require immediate treatment with glucagon or intravenous glucose and close monitoring for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Glucotrol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glipizida Glipizide Glipizidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glipizide is a sulfonylurea medication used in Type 2 Diabetes to sensitize pancreatic beta cells and stimulate insulin release.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Glipizide interact? Information: •Drug A: Buserelin •Drug B: Glipizide •Severity: MODERATE •Description: The therapeutic efficacy of Glipizide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Glipizide is a blood glucose-lowering agent. The initial onset of blood glucose-lowering effect occurs around 30 minutes post-administration with the duration of action lasting for about 12 to 24 hours. While the chronic use of glipizide does not result in elevations in the fasting insulin levels over time, the postprandial insulin response, or insulin response to a meal, is observed to be enhanced, even after 6 months of treatment. The main therapeutic actions of glipizide primarily occur at the pancreas where the insulin release is stimulated, but glipizide also mediates some extrapancreatic effects, such as the promotion of insulin signaling effects on the muscles, fat, or liver cells. Due to its action on the endogenous cells, sulfonylureas including glipizide is associated with a risk for developing hypoglycemia and weight gain in patients receiving the drug. Chronic administration of glipizide may result in down-regulation of the sulfonylurea receptors on pancreatic beta cells, which are molecular targets of the drug, leading to a reduced effect on insulin secretion. Like other sulfonylureas, glipizide may work on pancreatic delta (δ) cells and alpha (α) cells to stimulate the secretion of somatostatin and suppress the secretion of glucagon, which are peptide hormones that regulate neuroendocrine and metabolic pathways. Other than its primary action on the pancreas, glipizide also exerts other biological actions outside of the pancreas, or "extrapancreatic effects", which is similar to other members of the sulfonylurea drug class. Glipizide may enhance the glucose uptake into the skeletal muscles and potentiate the action of insulin in the liver. Other effects include inhibited lipolysis in the liver and adipose tissue, inhibited hepatic glucose output, and increased uptake and oxidation of glucose. It has also been demonstrated by several studies that the chronic therapeutic use of sulfonylureas may result in an increase in insulin receptors expressed on monocytes, adipocytes, and erythrocytes. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence worldwide. Characterized by higher-than-normal levels of blood glucose, T2DM is a complex disorder that arises from the interaction between genetic, environmental and behavioral risk factors. Insulin is a peptide hormone that plays a critical role in regulating blood glucose levels. In response to high blood glucose levels, insulin promotes the uptake of glucose into the liver, muscle cells, and fat cells for storage. Although there are multiple events occurring that lead to the pathophysiology of T2DM, the disorder mainly involves insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual failure of beta cells of pancreatic islets that normally produce insulin. Early management with lifestyle intervention, such as controlled diet and exercise, is critical in reducing the risk of long-term secondary complications, such as cardiovascular mortality. Glipizide, like other sulfonylurea drugs, is an insulin secretagogue, which works by stimulating the insulin release from the pancreatic beta cells thereby increasing the plasma concentrations of insulin. Thus, the main therapeutic action of the drug depends on the functional beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor expressed on the pancreatic beta-cell plasma membrane, leading to the closure of the ATP-sensitive potassium channel and reduced potassium conductance. This results in depolarization of the pancreatic beta cell and opening of the voltage-sensitive calcium channels, promoting calcium ion influx. Increased intracellular concentrations of calcium ions in beta cells stimulates the secretion, or exocytosis, of insulin granules from the cells. Apart from this main mechanism of action, the blood-glucose-lowering effect of glipizide involves increased peripheral glucose utilization via stimulating hepatic gluconeogenesis and by increasing the number and sensitivity of insulin receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. The absolute bioavailability of glipizide in patients with type 2 diabetes receiving a single oral dose was 100%. The maximum plasma concentrations are expected to be reached within 6 to 12 hours following initial dosing. The steady-state plasma concentrations of glipizide from extended-release oral formulations are maintained over the 24-hour dosing interval. In healthy volunteers, the absorption of glipizide was delayed by the presence of food but the total absorption was unaffected. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean volume of distribution was approximately 10 L following administration of single intravenous doses in patients with type 2 diabetes mellitus. In mice and rat studies, the presence of the drug and its metabolites was none to minimal in the fetus of pregnant female animals. Other sulfonylurea drugs were shown to cross the placenta and enter breast milk thus the potential risk of glipizide in fetus or infants cannot be excluded. •Protein binding (Drug A): 15% •Protein binding (Drug B): Glipizide is about 98-99% bound to serum proteins, with albumin being the main plasma protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Glipizide is subject to hepatic metabolism, in which its major metabolites are formed from aromatic hydroxylation. These major metabolites are glipizide are reported to be pharmacologically inactive. In contrast, an acetylaminoethyl benzine derivative is formed as a minor metabolite which accounts for less than 2% of the initial dose and is reported to have one-tenth to one-third as much hypoglycemic activity as the parent compound. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Glipizide is mainly eliminated by hepatic biotransformation, where less than 10% of the initial dose of the drug can be detected in the urine and feces as unchanged glipizide. About 80% of the metabolites of glipizide is excreted in the urine while 10% is excreted in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total body clearance of glipizide was approximately 3 L/hr following administration of single intravenous doses in patients with type 2 diabetes mellitus. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In rats, the oral LD 50 is reported to be greater than 4000 mg/kg and the intraperitoneal LD 50 is 1200 mg/kg. The lowest published toxic dose (TDLo) via oral route in child was 379 μg/kg. Symptoms of overdose in sulfonylureas, including glipizide, may be related to severe hypoglycemia and may include coma, seizure, or other neurological impairment. These are symptoms of severe hypoglycemia and require immediate treatment with glucagon or intravenous glucose and close monitoring for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Glucotrol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glipizida Glipizide Glipizidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glipizide is a sulfonylurea medication used in Type 2 Diabetes to sensitize pancreatic beta cells and stimulate insulin release. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Gliquidone interact?

•Drug A: Buserelin •Drug B: Gliquidone •Severity: MODERATE •Description: The therapeutic efficacy of Gliquidone can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used in the treatment of diabetes mellitus type 2. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Gliquidone is an anti-diabetic drug in the sulfonylurea class. In patients with diabetes mellitus, there is a deficiency or absence of a hormone manufactured by the pancreas called insulin. Insulin is the main hormone responsible for the control of sugar in the blood. Gliquidone is an antidiabetic medication which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). It works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body which need it. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of gliquidone in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Gliquidone likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life was approximately 8 hours (range 5.7-9.4 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gliquidone is a sulfonylurea drug used in the management of diabetes mellitus type 2.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Gliquidone interact? Information: •Drug A: Buserelin •Drug B: Gliquidone •Severity: MODERATE •Description: The therapeutic efficacy of Gliquidone can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used in the treatment of diabetes mellitus type 2. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Gliquidone is an anti-diabetic drug in the sulfonylurea class. In patients with diabetes mellitus, there is a deficiency or absence of a hormone manufactured by the pancreas called insulin. Insulin is the main hormone responsible for the control of sugar in the blood. Gliquidone is an antidiabetic medication which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). It works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body which need it. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of gliquidone in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Gliquidone likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life was approximately 8 hours (range 5.7-9.4 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Gliquidone is a sulfonylurea drug used in the management of diabetes mellitus type 2. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Glyburide interact?

•Drug A: Buserelin •Drug B: Glyburide •Severity: MODERATE •Description: The therapeutic efficacy of Glyburide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Glyburide is indicated alone or as part of combination product with metformin, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Glyburide is a second generation sulfonylurea that stimulates insulin secretion through the closure of ATP-sensitive potassium channels on beta cells, raising intracellular potassium and calcium ion concentrations. Glibenclamide has a long duration of action as it is given once daily, and a wide therapeutic index as patients are started at doses as low as 0.75mg but that can increase as high as 10mg or more. Patients taking glyburide should be cautioned regarding an increased risk of cardiovascular mortality as seen with tolbutamide, another sulfonylurea. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Glyburide belongs to a class of drugs known as sulfonylureas. These drugs act by closing ATP-sensitive potassium channels on pancreatic beta cells. The ATP-sensitive potassium channels on beta cells are known as sulfonylurea receptor 1 (SUR1). Under low glucose concentrations, SUR1 remains open, allowing for potassium ion efflux to create a -70mV membrane potential. Normally SUR1 closes in response to high glucose concentrations, the membrane potential of the cells becomes less negative, the cell depolarizes, voltage gated calcium channels open, calcium ions enter the cell, and the increased intracellular calcium concentration stimulates the release of insulin containing granules. Glyburide bypasses this process by forcing SUR1 closed and stimulating increased insulin secretion. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Elderly patients taking glyburide reached a C max of 211-315ng/mL with a T max of 0.9-1.0h, while younger patients reached a C max of 144-302ng/mL with a T max of 1.3-3.0h. Patients taking glyburide have and AUC of 348ng*h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Elderly patients have a volume of distribution of 19.3-52.6L, while younger patients have a volume of distribution of 21.5-49.3L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Glyburide is 99.9% bound to protein in plasma with >98% accounted for by binding to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Glyburide is metabolized mainly by CYP3A4, followed by CYP2C9, CYP2C19, CYP3A7, and CYP3A5. These enzymes metabolize glyburide to 4-trans-hydroxycyclohexyl glyburide (M1), 4-cis-hydroxycyclohexyl glyburide (M2a), 3-cis-hydroxycyclohexyl glyburide (M2b), 3-trans-hydroxycyclohexyl glyburide (M3), 2-trans-hydroxycyclohexyl glyburide (M4), and ethylhydroxycyclohexyl glyburide (M5). The M1 and M2b metabolites are considered active, along with the parent molecule. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Unlike other sulfonylureas, glyburide is 50% excreted in the urine and 50% in the feces. Glyburide is mainly excreted as the metabolite 4-trans-hydroxyglyburide. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elderly patients have a terminal elimination half life of 4.0-13.4h, while younger patients have a terminal elimination half life of 4.0-13.9h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Elderly patients have a clearance of 2.70-3.55L/h, while younger patients have a clearance of 2.47-4.11L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in rats is >3200mg/kg, in mice is >1500mg/kg, in rabbits is >10,000mg/kg, and in guinea pigs is >1500mg/kg. Patients experiencing an overdose may present with hypoglycemia. Mild hypoglycemia should be treated with oral glucose and adjustments to drug doses or meal schedules. Severe hypoglycemia may present with coma, seizure, and neurological impairment. This should be treated immediately in hospital with intravenous glucose and monitoring for 24-48 hours. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diabeta, Glucovance, Glynase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glibenclamida Glibenclamide Glibenclamidum Glyburide •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glyburide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Glyburide interact? Information: •Drug A: Buserelin •Drug B: Glyburide •Severity: MODERATE •Description: The therapeutic efficacy of Glyburide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Glyburide is indicated alone or as part of combination product with metformin, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Glyburide is a second generation sulfonylurea that stimulates insulin secretion through the closure of ATP-sensitive potassium channels on beta cells, raising intracellular potassium and calcium ion concentrations. Glibenclamide has a long duration of action as it is given once daily, and a wide therapeutic index as patients are started at doses as low as 0.75mg but that can increase as high as 10mg or more. Patients taking glyburide should be cautioned regarding an increased risk of cardiovascular mortality as seen with tolbutamide, another sulfonylurea. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Glyburide belongs to a class of drugs known as sulfonylureas. These drugs act by closing ATP-sensitive potassium channels on pancreatic beta cells. The ATP-sensitive potassium channels on beta cells are known as sulfonylurea receptor 1 (SUR1). Under low glucose concentrations, SUR1 remains open, allowing for potassium ion efflux to create a -70mV membrane potential. Normally SUR1 closes in response to high glucose concentrations, the membrane potential of the cells becomes less negative, the cell depolarizes, voltage gated calcium channels open, calcium ions enter the cell, and the increased intracellular calcium concentration stimulates the release of insulin containing granules. Glyburide bypasses this process by forcing SUR1 closed and stimulating increased insulin secretion. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Elderly patients taking glyburide reached a C max of 211-315ng/mL with a T max of 0.9-1.0h, while younger patients reached a C max of 144-302ng/mL with a T max of 1.3-3.0h. Patients taking glyburide have and AUC of 348ng*h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Elderly patients have a volume of distribution of 19.3-52.6L, while younger patients have a volume of distribution of 21.5-49.3L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Glyburide is 99.9% bound to protein in plasma with >98% accounted for by binding to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Glyburide is metabolized mainly by CYP3A4, followed by CYP2C9, CYP2C19, CYP3A7, and CYP3A5. These enzymes metabolize glyburide to 4-trans-hydroxycyclohexyl glyburide (M1), 4-cis-hydroxycyclohexyl glyburide (M2a), 3-cis-hydroxycyclohexyl glyburide (M2b), 3-trans-hydroxycyclohexyl glyburide (M3), 2-trans-hydroxycyclohexyl glyburide (M4), and ethylhydroxycyclohexyl glyburide (M5). The M1 and M2b metabolites are considered active, along with the parent molecule. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Unlike other sulfonylureas, glyburide is 50% excreted in the urine and 50% in the feces. Glyburide is mainly excreted as the metabolite 4-trans-hydroxyglyburide. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elderly patients have a terminal elimination half life of 4.0-13.4h, while younger patients have a terminal elimination half life of 4.0-13.9h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Elderly patients have a clearance of 2.70-3.55L/h, while younger patients have a clearance of 2.47-4.11L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in rats is >3200mg/kg, in mice is >1500mg/kg, in rabbits is >10,000mg/kg, and in guinea pigs is >1500mg/kg. Patients experiencing an overdose may present with hypoglycemia. Mild hypoglycemia should be treated with oral glucose and adjustments to drug doses or meal schedules. Severe hypoglycemia may present with coma, seizure, and neurological impairment. This should be treated immediately in hospital with intravenous glucose and monitoring for 24-48 hours. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diabeta, Glucovance, Glynase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glibenclamida Glibenclamide Glibenclamidum Glyburide •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Glyburide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Goserelin interact?

•Drug A: Buserelin •Drug B: Goserelin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Goserelin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Goserelin is indicated for: Use in combination with flutamide for the management of locally confined carcinoma of the prostate Palliative treatment of advanced carcinoma of the prostate The management of endometriosis Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding Use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The pharmacokinetics of goserelin have been determined in both male and female healthy volunteers and patients. In these studies, goserelin was administered as a single 250µg (aqueous solution) dose and as a single or multiple 3.6 mg depot dose by subcutaneous route. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Goserelin is a synthetic decapeptide analogue of LHRH. Goserelin acts as a potent inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. The result is sustained suppression of LH and serum testosterone levels. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Inactive orally, rapidly absorbed following subcutaneous administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 44.1 ± 13.6 L [subcutaneous administration of 250 mcg] •Protein binding (Drug A): 15% •Protein binding (Drug B): 27.3% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 4-5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 121 +/- 42.4 mL/min [prostate cancer with 10.8 mg depot] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No experience of overdosage from clinical trials. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zoladex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Goserelin is a synthetic analog of luteinizing hormone-releasing hormone used to treat breast cancer and prostate cancer by reducing secretion of gonadotropins from the pituitary.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Goserelin interact? Information: •Drug A: Buserelin •Drug B: Goserelin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Goserelin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Goserelin is indicated for: Use in combination with flutamide for the management of locally confined carcinoma of the prostate Palliative treatment of advanced carcinoma of the prostate The management of endometriosis Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding Use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The pharmacokinetics of goserelin have been determined in both male and female healthy volunteers and patients. In these studies, goserelin was administered as a single 250µg (aqueous solution) dose and as a single or multiple 3.6 mg depot dose by subcutaneous route. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Goserelin is a synthetic decapeptide analogue of LHRH. Goserelin acts as a potent inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. The result is sustained suppression of LH and serum testosterone levels. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Inactive orally, rapidly absorbed following subcutaneous administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 44.1 ± 13.6 L [subcutaneous administration of 250 mcg] •Protein binding (Drug A): 15% •Protein binding (Drug B): 27.3% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 4-5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 121 +/- 42.4 mL/min [prostate cancer with 10.8 mg depot] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No experience of overdosage from clinical trials. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zoladex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Goserelin is a synthetic analog of luteinizing hormone-releasing hormone used to treat breast cancer and prostate cancer by reducing secretion of gonadotropins from the pituitary. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Granisetron interact?

•Drug A: Buserelin •Drug B: Granisetron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Granisetron. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy (including high dose cisplatin), postoperation, and radiation (including total body irradiation and daily fractionated abdominal radiation). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Granisetron is a selective inhibitor of type 3 serotonergic (5-HT 3 ) receptors. Granisetron has little or no affinity for other serotonin receptors, including 5-HT 1, 5-HT 1A, 5-HT 1B/C, or 5-HT 2; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine D 2 receptors; for histamine H 1 receptors; for benzodiazepine receptors; for picrotoxin receptors; or for opioid receptors. In most human studies, granisetron has had little effect on blood pressure, heart rate, or electrocardiogram (ECG). The drug is structurally and pharmacologically related to ondansetron, another selective inhibitor of 5-HT 3 receptors. The serontonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Granisetron is a potent, selective antagonist of 5-HT 3 receptors. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 65% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic; undergoes N -demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may have 5-HT 3 receptor antagonist activity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 4-6 hours in healthy patients, 9-12 hours in cancer patients •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.52 L/h/kg [Cancer Patients with 1 mg bid for 7 days] 0.41 L/h/kg [Healthy subject with a single 1 mg dose] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 >2000 mg/kg (rat, oral) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sancuso, Sustol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Granisetron is a 5HT3 antagonist used to treat nausea and vomiting in cancer therapy and postoperatively.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Granisetron interact? Information: •Drug A: Buserelin •Drug B: Granisetron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Granisetron. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy (including high dose cisplatin), postoperation, and radiation (including total body irradiation and daily fractionated abdominal radiation). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Granisetron is a selective inhibitor of type 3 serotonergic (5-HT 3 ) receptors. Granisetron has little or no affinity for other serotonin receptors, including 5-HT 1, 5-HT 1A, 5-HT 1B/C, or 5-HT 2; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine D 2 receptors; for histamine H 1 receptors; for benzodiazepine receptors; for picrotoxin receptors; or for opioid receptors. In most human studies, granisetron has had little effect on blood pressure, heart rate, or electrocardiogram (ECG). The drug is structurally and pharmacologically related to ondansetron, another selective inhibitor of 5-HT 3 receptors. The serontonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Granisetron is a potent, selective antagonist of 5-HT 3 receptors. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 65% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic; undergoes N -demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may have 5-HT 3 receptor antagonist activity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 4-6 hours in healthy patients, 9-12 hours in cancer patients •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.52 L/h/kg [Cancer Patients with 1 mg bid for 7 days] 0.41 L/h/kg [Healthy subject with a single 1 mg dose] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 >2000 mg/kg (rat, oral) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sancuso, Sustol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Granisetron is a 5HT3 antagonist used to treat nausea and vomiting in cancer therapy and postoperatively. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Haloperidol interact?

•Drug A: Buserelin •Drug B: Haloperidol •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Haloperidol. •Extended Description: There is a risk for QTc prolongation with haloperidol monotherapy; therefore, co-administration with other QTc prolonging agents may potentiate this adverse effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Haloperidol is indicated for a number of conditions including for the treatment of schizophrenia, for the manifestations of psychotic disorders, for the control of tics and vocal utterances of Tourette’s Disorder in children and adults, for treatment of severe behavior problems in children of combative, explosive hyperexcitability (which cannot be accounted for by immediate provocation). Haloperidol is also indicated in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. Haloperidol should be reserved for these two groups of children only after failure to respond to psychotherapy or medications other than antipsychotics. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation. However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes. Compared to the lower-potency first-generation antipsychotics such as Chlorpromazine, Zuclopenthixol, Fluphenazine, and Methotrimeprazine, haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol. Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain. While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor. Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as Risperidone. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Haloperidol is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics. Studies have found a wide variance in pharmacokinetic values for orally administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h [range 14.89-120.96 μg/L•h] reported for AUC. Haloperidol is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75%. After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability following intramuscular administration is higher than that for oral administration. Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution was found to range from 9.5-21.7 L/kg. This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): Studies have found that free fraction of haloperidol in human plasma is 7.5-11.6%. This was found to be comparable among healthy adults, young adults, elderly patients with schizophrenia, and even in patients with liver cirrhosis. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Haloperidol is extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in urine. In humans, haloperidol is biotransformed to various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridinium metabolites, and haloperidol glucuronide. In psychiatric patients treated regularly with haloperidol, the concentration of haloperidol glucuronide in plasma is the highest among the metabolites, followed, in rank order, by unchanged haloperidol, reduced haloperidol and reduced haloperidol glucuronide. The drug is thought to be metabolized primarily by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming hydroxyhaloperidol. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) including CYP3A4 and CYP2D6, carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes. The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans. The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude. This suggests that the same enzyme system is responsible for the above three metabolic reactions. In vivo human studies on haloperidol metabolism have shown that the glucuronidation of haloperidol accounts for 50 to 60% of haloperidol biotransformation and that approximately 23% of the biotransformation was accounted for by the reduction pathway. The remaining 20 to 30% ofthe biotransformation of haloperidol would be via N-dealkylation and pyridinium formation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral administration, the half-life was found to be 14.5-36.7 hours. Following intramuscular injection, mean half-life was found to be 20.7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance was found to be 141.65 L/h (range 41.34 to 335.80 L/h). Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C YP2D6 enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. Genetic polymorphism of CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute oral toxicity (LD50): 71 mg/kg in rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Haldol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Haloperidol Haloperidolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Haloperidol is an antipsychotic agent used to treat schizophrenia and other psychoses, as well as symptoms of agitation, irritability, and delirium.

There is a risk for QTc prolongation with haloperidol monotherapy; therefore, co-administration with other QTc prolonging agents may potentiate this adverse effect. The severity of the interaction is moderate.

Question: Does Buserelin and Haloperidol interact? Information: •Drug A: Buserelin •Drug B: Haloperidol •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Haloperidol. •Extended Description: There is a risk for QTc prolongation with haloperidol monotherapy; therefore, co-administration with other QTc prolonging agents may potentiate this adverse effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Haloperidol is indicated for a number of conditions including for the treatment of schizophrenia, for the manifestations of psychotic disorders, for the control of tics and vocal utterances of Tourette’s Disorder in children and adults, for treatment of severe behavior problems in children of combative, explosive hyperexcitability (which cannot be accounted for by immediate provocation). Haloperidol is also indicated in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. Haloperidol should be reserved for these two groups of children only after failure to respond to psychotherapy or medications other than antipsychotics. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation. However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes. Compared to the lower-potency first-generation antipsychotics such as Chlorpromazine, Zuclopenthixol, Fluphenazine, and Methotrimeprazine, haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol. Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain. While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor. Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as Risperidone. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Haloperidol is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics. Studies have found a wide variance in pharmacokinetic values for orally administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h [range 14.89-120.96 μg/L•h] reported for AUC. Haloperidol is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75%. After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability following intramuscular administration is higher than that for oral administration. Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution was found to range from 9.5-21.7 L/kg. This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): Studies have found that free fraction of haloperidol in human plasma is 7.5-11.6%. This was found to be comparable among healthy adults, young adults, elderly patients with schizophrenia, and even in patients with liver cirrhosis. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Haloperidol is extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in urine. In humans, haloperidol is biotransformed to various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridinium metabolites, and haloperidol glucuronide. In psychiatric patients treated regularly with haloperidol, the concentration of haloperidol glucuronide in plasma is the highest among the metabolites, followed, in rank order, by unchanged haloperidol, reduced haloperidol and reduced haloperidol glucuronide. The drug is thought to be metabolized primarily by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming hydroxyhaloperidol. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) including CYP3A4 and CYP2D6, carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes. The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans. The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude. This suggests that the same enzyme system is responsible for the above three metabolic reactions. In vivo human studies on haloperidol metabolism have shown that the glucuronidation of haloperidol accounts for 50 to 60% of haloperidol biotransformation and that approximately 23% of the biotransformation was accounted for by the reduction pathway. The remaining 20 to 30% ofthe biotransformation of haloperidol would be via N-dealkylation and pyridinium formation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral administration, the half-life was found to be 14.5-36.7 hours. Following intramuscular injection, mean half-life was found to be 20.7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance was found to be 141.65 L/h (range 41.34 to 335.80 L/h). Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C YP2D6 enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. Genetic polymorphism of CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute oral toxicity (LD50): 71 mg/kg in rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Haldol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Haloperidol Haloperidolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Haloperidol is an antipsychotic agent used to treat schizophrenia and other psychoses, as well as symptoms of agitation, irritability, and delirium. Output: There is a risk for QTc prolongation with haloperidol monotherapy; therefore, co-administration with other QTc prolonging agents may potentiate this adverse effect. The severity of the interaction is moderate.

Does Buserelin and Histrelin interact?

•Drug A: Buserelin •Drug B: Histrelin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Histrelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As the product Supprelin LA (FDA), histrelin is indicated for the treatment of children with central precocious puberty (CPP). As the product Vantas (FDA), histrelin is indicated for the palliative treatment of advanced prostate cancer. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Histrelin inhibits gonadotropin secretion through the reversible down-regulation of gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and desensitization of the pituitary gonadotropes. In pediatric patients with central precocious puberty (CPP), long-term treatment with histrelin acetate suppresses the luteinizing hormone (LH) response to GnRH, causing LH levels to decrease to prepubertal levels within one month of treatment. This reduces ovarian and testicular steroidogenesis and slows down linear growth velocity, improving the chance of attaining predicted adult height. When given orally, histrelin acetate is not active. Both histrelin products (Vantas and Supprelin LA from Endo Pharmaceuticals) cause a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Laboratory tests are also recommended in order to monitor hormone levels. For pediatric patients with central precocious puberty (CPP) using histrelin (Supprelin LA, Endo Pharmaceuticals), LH, follicle-stimulating hormone and estradiol or testosterone should be monitored. In patients with advanced prostate cancer using histrelin (Vantas, Endo Pharmaceuticals), testosterone and prostate-specific antigen should be measured periodically. Issues such as breakage during insertion and difficulty locating and removing implants have been reported. The Supprelin LA (Endo Pharmaceuticals) product label alerts users about psychiatric events, convulsions and cases of pseudotumor cerebri (idiopathic intracranial hypertension) that have been reported in patients receiving GnRH agonists. The Vantas (Endo Pharmaceuticals) product label alerts users about cases of spinal cord compression and urinary tract obstruction, and an increased risk of hyperglycemia/diabetes and cardiovascular disease in men receiving GnRH agonists. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Histrelin is a gonadotropin-releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin. GnRH binds to the GnRH receptor located on the pituitary gonadotrophs, and this leads to the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the regulation of sexual maturation and reproductive function. When administered as an implant, histrelin is delivered in continuous therapeutic doses. As a GnRH agonist, this drug binds and, at first, activates the GnRH receptor. This increases the circulating levels of LH and FSH, leading to a transient increase in the concentration of gonadal steroids (testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females). However, the continuous administration of histrelin induces the reversible down-regulation of the GnRH receptor and the desensitization of pituitary gonadotropes, which reduce LH and FSH levels. Pediatric patients with central precocious puberty (CPP) have a lower height potential. When treated with histrelin, LH levels in CPP are lowered, reducing the concentration of sex steroids. In adult males with advanced prostate cancer, histrelin reduces testosterone production to castration levels, hindering the growth of prostate cancer cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Advanced prostate cancer patients (n = 17) that received a subcutaneous histrelin implant (Vantas, Endo Pharmaceuticals) had peak serum concentrations of 1.10 ± 0.375 ng/mL (mean ± SD) at 12 hours. The continuous subcutaneous release of the histrelin implant was confirmed, as serum levels were sustained throughout the 52-week dosing period. At the end of the 52-week period, the mean serum histrelin concentration was 0.13 ± 0.065 ng/mL. In patients that received a second implant at the end of the 52-week period, the serum histrelin concentration in the first eight weeks was similar to the one detected with the first implant. On average, the residual drug content of 41 histrelin implants (Vantas, Endo Pharmaceuticals) was 56.7 ± 7.71 mcg/day over 52 weeks. Compared to healthy male volunteers that received a subcutaneous bolus dose, the relative bioavailability of histrelin in patients with prostate cancer and normal renal and hepatic function was 92%. In children with central precocious puberty (CPP, n=47) that received a subcutaneous histrelin implant (Supprelin LA, Endo Pharmaceuticals), the median maximum serum histrelin concentration over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There were no pharmacokinetic differences between patients previously treated with luteinizing hormone-releasing hormone (LHRH) agonists and those that had not. Food-drug interaction studies have not been performed for histrelin products. Serum histrelin concentrations are 50% higher in prostate cancer patients with mild to severe renal impairment compared to those with no renal or hepatic impairment; however, this difference is not considered clinically relevant. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of histrelin following a subcutaneous bolus dose of histrelin (Vantas, Endo Pharmaceuticals, 500 mcg) in healthy volunteers was 58.4 ± 7.86 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): In an in vitro measurement, the fraction of histrelin (Vantas, Endo Pharmaceuticals) unbound in plasma was 29.5% ± 8.9% (mean ± SD). •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): As a synthetic peptide, histrelin is expected to be metabolized by proteases throughout the body. This will likely result in several peptide fragments produced by hydrolysis. In an in vitro drug metabolism study using human hepatocytes, a single histrelin metabolite resulting from C-terminal dealkylation was identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Drug excretion studies have not been performed for histrelin. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In healthy volunteers administered a subcutaneous bolus dose of histrelin, the terminal half-life was 3.92 ± 1.01 hr (mean ± SD). •Clearance (Drug A): No clearance available •Clearance (Drug B): In prostate cancer patients (n=17) administered a histrelin implant (Vantas, Endo Pharmaceuticals) the apparent clearance was 174 ± 56.5 mL/min (mean ± SD). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There were no signs of systemic toxicity in animals injected with up to 200 mcg/kg (rats, rabbits), or 2000 mcg/kg (mice) of histrelin acetate. These concentrations represent 20 to 200 times the maximal recommended human dose of 10 mcg/kg/day. Patients receiving one, two or four histrelin implants (Vantas, Endo Pharmaceuticals) had similar adverse event profiles. No overdose cases were reported in the clinical trials of the histrelin product Supprelin LA (Vantas, Endo Pharmaceuticals). The administration of high doses of histrelin in animal studies was associated with the expected pharmacological effects. Since both products of histrelin are administered using implants that deliver a constant dose, accidental or intentional overdose is unlikely. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Supprelin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Histrelin histrelina histreline histrelinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Histrelin is a GnRH agonist found in subcutaneous implants used for the treatment of pediatric patients with central precocious puberty and the palliative treatment of advanced prostate cancer.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Histrelin interact? Information: •Drug A: Buserelin •Drug B: Histrelin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Histrelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As the product Supprelin LA (FDA), histrelin is indicated for the treatment of children with central precocious puberty (CPP). As the product Vantas (FDA), histrelin is indicated for the palliative treatment of advanced prostate cancer. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Histrelin inhibits gonadotropin secretion through the reversible down-regulation of gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and desensitization of the pituitary gonadotropes. In pediatric patients with central precocious puberty (CPP), long-term treatment with histrelin acetate suppresses the luteinizing hormone (LH) response to GnRH, causing LH levels to decrease to prepubertal levels within one month of treatment. This reduces ovarian and testicular steroidogenesis and slows down linear growth velocity, improving the chance of attaining predicted adult height. When given orally, histrelin acetate is not active. Both histrelin products (Vantas and Supprelin LA from Endo Pharmaceuticals) cause a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Laboratory tests are also recommended in order to monitor hormone levels. For pediatric patients with central precocious puberty (CPP) using histrelin (Supprelin LA, Endo Pharmaceuticals), LH, follicle-stimulating hormone and estradiol or testosterone should be monitored. In patients with advanced prostate cancer using histrelin (Vantas, Endo Pharmaceuticals), testosterone and prostate-specific antigen should be measured periodically. Issues such as breakage during insertion and difficulty locating and removing implants have been reported. The Supprelin LA (Endo Pharmaceuticals) product label alerts users about psychiatric events, convulsions and cases of pseudotumor cerebri (idiopathic intracranial hypertension) that have been reported in patients receiving GnRH agonists. The Vantas (Endo Pharmaceuticals) product label alerts users about cases of spinal cord compression and urinary tract obstruction, and an increased risk of hyperglycemia/diabetes and cardiovascular disease in men receiving GnRH agonists. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Histrelin is a gonadotropin-releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin. GnRH binds to the GnRH receptor located on the pituitary gonadotrophs, and this leads to the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the regulation of sexual maturation and reproductive function. When administered as an implant, histrelin is delivered in continuous therapeutic doses. As a GnRH agonist, this drug binds and, at first, activates the GnRH receptor. This increases the circulating levels of LH and FSH, leading to a transient increase in the concentration of gonadal steroids (testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females). However, the continuous administration of histrelin induces the reversible down-regulation of the GnRH receptor and the desensitization of pituitary gonadotropes, which reduce LH and FSH levels. Pediatric patients with central precocious puberty (CPP) have a lower height potential. When treated with histrelin, LH levels in CPP are lowered, reducing the concentration of sex steroids. In adult males with advanced prostate cancer, histrelin reduces testosterone production to castration levels, hindering the growth of prostate cancer cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Advanced prostate cancer patients (n = 17) that received a subcutaneous histrelin implant (Vantas, Endo Pharmaceuticals) had peak serum concentrations of 1.10 ± 0.375 ng/mL (mean ± SD) at 12 hours. The continuous subcutaneous release of the histrelin implant was confirmed, as serum levels were sustained throughout the 52-week dosing period. At the end of the 52-week period, the mean serum histrelin concentration was 0.13 ± 0.065 ng/mL. In patients that received a second implant at the end of the 52-week period, the serum histrelin concentration in the first eight weeks was similar to the one detected with the first implant. On average, the residual drug content of 41 histrelin implants (Vantas, Endo Pharmaceuticals) was 56.7 ± 7.71 mcg/day over 52 weeks. Compared to healthy male volunteers that received a subcutaneous bolus dose, the relative bioavailability of histrelin in patients with prostate cancer and normal renal and hepatic function was 92%. In children with central precocious puberty (CPP, n=47) that received a subcutaneous histrelin implant (Supprelin LA, Endo Pharmaceuticals), the median maximum serum histrelin concentration over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There were no pharmacokinetic differences between patients previously treated with luteinizing hormone-releasing hormone (LHRH) agonists and those that had not. Food-drug interaction studies have not been performed for histrelin products. Serum histrelin concentrations are 50% higher in prostate cancer patients with mild to severe renal impairment compared to those with no renal or hepatic impairment; however, this difference is not considered clinically relevant. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of histrelin following a subcutaneous bolus dose of histrelin (Vantas, Endo Pharmaceuticals, 500 mcg) in healthy volunteers was 58.4 ± 7.86 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): In an in vitro measurement, the fraction of histrelin (Vantas, Endo Pharmaceuticals) unbound in plasma was 29.5% ± 8.9% (mean ± SD). •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): As a synthetic peptide, histrelin is expected to be metabolized by proteases throughout the body. This will likely result in several peptide fragments produced by hydrolysis. In an in vitro drug metabolism study using human hepatocytes, a single histrelin metabolite resulting from C-terminal dealkylation was identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Drug excretion studies have not been performed for histrelin. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In healthy volunteers administered a subcutaneous bolus dose of histrelin, the terminal half-life was 3.92 ± 1.01 hr (mean ± SD). •Clearance (Drug A): No clearance available •Clearance (Drug B): In prostate cancer patients (n=17) administered a histrelin implant (Vantas, Endo Pharmaceuticals) the apparent clearance was 174 ± 56.5 mL/min (mean ± SD). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There were no signs of systemic toxicity in animals injected with up to 200 mcg/kg (rats, rabbits), or 2000 mcg/kg (mice) of histrelin acetate. These concentrations represent 20 to 200 times the maximal recommended human dose of 10 mcg/kg/day. Patients receiving one, two or four histrelin implants (Vantas, Endo Pharmaceuticals) had similar adverse event profiles. No overdose cases were reported in the clinical trials of the histrelin product Supprelin LA (Vantas, Endo Pharmaceuticals). The administration of high doses of histrelin in animal studies was associated with the expected pharmacological effects. Since both products of histrelin are administered using implants that deliver a constant dose, accidental or intentional overdose is unlikely. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Supprelin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Histrelin histrelina histreline histrelinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Histrelin is a GnRH agonist found in subcutaneous implants used for the treatment of pediatric patients with central precocious puberty and the palliative treatment of advanced prostate cancer. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Hydrochlorothiazide interact?

•Drug A: Buserelin •Drug B: Hydrochlorothiazide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Hydrochlorothiazide is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Hydrochlorothiazide is indicated alone or in combination for the management of edema associated with congestive heart failure, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and corticosteroid and estrogen therapy. Hydrochlorothiazide is also indicated alone or in combination for the management of hypertension. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T max of 1-5 hours, and a C max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C max is 20% lower, and T max increases from 1.6 to 2.9 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Hydrochlorothiazide is 40-68% protein bound in plasma. Hydrochlorothiazide has been shown to bind to human serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hydrochlorothiazide is not metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The plasma half life of hydrochlorothiazide is 5.6-14.8h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 of hydrochlorothiazide is >10g/kg in mice and rats. Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Accuretic, Actelsar Hct, Aldactazide, Altace HCT, Atacand, Atacand Hct, Avalide, Benicar Hct, Diovan Hct, Exforge Hct, Hyzaar, Ifirmacombi, Karvezide, Lopressor Hct, Lotensin Hct, Maxzide, Micardis-hct, Olmetec Plus, Tekturna Hct, Teveten HCT, Tribenzor, Urozide, Vaseretic, Viskazide, Zestoretic, Ziac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hydrochlorothiazide is a thiazide diuretic used to treat edema associated with a number of conditions, and hypertension.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Hydrochlorothiazide interact? Information: •Drug A: Buserelin •Drug B: Hydrochlorothiazide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Hydrochlorothiazide is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Hydrochlorothiazide is indicated alone or in combination for the management of edema associated with congestive heart failure, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and corticosteroid and estrogen therapy. Hydrochlorothiazide is also indicated alone or in combination for the management of hypertension. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T max of 1-5 hours, and a C max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C max is 20% lower, and T max increases from 1.6 to 2.9 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Hydrochlorothiazide is 40-68% protein bound in plasma. Hydrochlorothiazide has been shown to bind to human serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hydrochlorothiazide is not metabolized. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The plasma half life of hydrochlorothiazide is 5.6-14.8h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 of hydrochlorothiazide is >10g/kg in mice and rats. Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Accuretic, Actelsar Hct, Aldactazide, Altace HCT, Atacand, Atacand Hct, Avalide, Benicar Hct, Diovan Hct, Exforge Hct, Hyzaar, Ifirmacombi, Karvezide, Lopressor Hct, Lotensin Hct, Maxzide, Micardis-hct, Olmetec Plus, Tekturna Hct, Teveten HCT, Tribenzor, Urozide, Vaseretic, Viskazide, Zestoretic, Ziac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hydrochlorothiazide is a thiazide diuretic used to treat edema associated with a number of conditions, and hypertension. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Hydroxychloroquine interact?

•Drug A: Buserelin •Drug B: Hydroxychloroquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Hydroxychloroquine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Hydroxychloroquine is indicated for the prophylaxis of malaria where chloroquine resistance is not reported, treatment of uncomplicated malaria (caused by P. falciparum, P. malariae, P. ovale, or P. vivax ), chronic discoid lupus erythematosus, systemic lupus erythematosus, acute rheumatoid arthritis, and chronic rheumatoid arthritis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hydroxychloroquine affects the function of lysosomes in humans as well as plasmodia. Altering the pH of the lysosomes reduces low-affinity self-antigen presentation in autoimmune diseases and interferes with the ability of plasmodia to proteolyze hemoglobin for their energy requirements. Hydroxychloroquine has a long duration of action as it may be taken on a weekly basis for some indications. Hydroxychloroquine may lead to severe hypoglycemia and so diabetic patients are advised to monitor their blood glucose levels. Hydroxychloroquine is active against the erythrocytic forms of chloroquine-sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale. Hydroxychloroquine is not effective against malaria in areas where chloroquine resistance has been reported. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Hydroxychloroquine can also interfere with the action of parasitic heme polymerase, an enzyme that uses ferriprotoporphyrin IX (FP) released from hemoglobin as a substrate to form beta-hematin. By reducing the activity of heme polymerase without inhibiting the release of FP, hydroxychloroquine leads to the accumulation of FP in a toxic form. Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors. The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell. Hydroxychloroquine inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Hydroxychloroquine is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a single 200 mg oral dose of hydroxychloroquine to healthy male volunteers, whole blood hydroxychloroquine C max was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours). Following a single oral hydroxychloroquine dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to the administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Hydroxychloroquine is extensively distributed to tissues; it has a volume of distribution of 5522L from blood and 44,257L from plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): The S enantiomer of hydroxychloroquine is 64% protein bound in plasma. It is 50% bound to serum albumin and 29% bound to alpha-1-acid glycoprotein. The R enantiomer is 37% protein bound in plasma. It is 29% bound to serum albumin and 41% bound to alpha-1-acid glycoprotein. In total, hydroxychloroquine is 50% protein bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine. Desethylhydroxychloroquine is the major metabolite. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): A half-life of 123.5 days in plasma was observed following a single 200 mg oral PLAQUENIL dose to healthy male volunteers. Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of hydroxychloroquine is 96mL/min. Renal clearance of unchanged drug was approximately 16% to 30%. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation. This may progress to sudden respiratory and cardiac arrest. Overdose should be treated with immediate gastric lavage and activated charcoal at a dose of at least 5 times the hydroxychloroquine dose within 30 minutes. Parenteral diazepam may be given to treat cardiotoxicity, transfusion may reduce serum concentrations of drug, patients should be monitored for at least 6 hours, fluids should be given, and ammonium chloride should be given to acidify urine and promote urinary excretion. Patients may also be given epinephrine. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Plaquenil, Sovuna •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Hidroxicloroquina Hydroxychloroquine Hydroxychloroquinum Oxichlorochine Oxichloroquine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hydroxychloroquine is an antimalarial medication used to treat uncomplicated cases of malaria and for chemoprophylaxis in specific regions. Also a disease modifying anti-rheumatic drug (DMARD) indicated for treatment of rheumatoid arthritis and lupus erythematosus.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Hydroxychloroquine interact? Information: •Drug A: Buserelin •Drug B: Hydroxychloroquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Hydroxychloroquine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Hydroxychloroquine is indicated for the prophylaxis of malaria where chloroquine resistance is not reported, treatment of uncomplicated malaria (caused by P. falciparum, P. malariae, P. ovale, or P. vivax ), chronic discoid lupus erythematosus, systemic lupus erythematosus, acute rheumatoid arthritis, and chronic rheumatoid arthritis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hydroxychloroquine affects the function of lysosomes in humans as well as plasmodia. Altering the pH of the lysosomes reduces low-affinity self-antigen presentation in autoimmune diseases and interferes with the ability of plasmodia to proteolyze hemoglobin for their energy requirements. Hydroxychloroquine has a long duration of action as it may be taken on a weekly basis for some indications. Hydroxychloroquine may lead to severe hypoglycemia and so diabetic patients are advised to monitor their blood glucose levels. Hydroxychloroquine is active against the erythrocytic forms of chloroquine-sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale. Hydroxychloroquine is not effective against malaria in areas where chloroquine resistance has been reported. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Hydroxychloroquine can also interfere with the action of parasitic heme polymerase, an enzyme that uses ferriprotoporphyrin IX (FP) released from hemoglobin as a substrate to form beta-hematin. By reducing the activity of heme polymerase without inhibiting the release of FP, hydroxychloroquine leads to the accumulation of FP in a toxic form. Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors. The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell. Hydroxychloroquine inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Hydroxychloroquine is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a single 200 mg oral dose of hydroxychloroquine to healthy male volunteers, whole blood hydroxychloroquine C max was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours). Following a single oral hydroxychloroquine dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to the administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Hydroxychloroquine is extensively distributed to tissues; it has a volume of distribution of 5522L from blood and 44,257L from plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): The S enantiomer of hydroxychloroquine is 64% protein bound in plasma. It is 50% bound to serum albumin and 29% bound to alpha-1-acid glycoprotein. The R enantiomer is 37% protein bound in plasma. It is 29% bound to serum albumin and 41% bound to alpha-1-acid glycoprotein. In total, hydroxychloroquine is 50% protein bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine. Desethylhydroxychloroquine is the major metabolite. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): A half-life of 123.5 days in plasma was observed following a single 200 mg oral PLAQUENIL dose to healthy male volunteers. Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of hydroxychloroquine is 96mL/min. Renal clearance of unchanged drug was approximately 16% to 30%. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation. This may progress to sudden respiratory and cardiac arrest. Overdose should be treated with immediate gastric lavage and activated charcoal at a dose of at least 5 times the hydroxychloroquine dose within 30 minutes. Parenteral diazepam may be given to treat cardiotoxicity, transfusion may reduce serum concentrations of drug, patients should be monitored for at least 6 hours, fluids should be given, and ammonium chloride should be given to acidify urine and promote urinary excretion. Patients may also be given epinephrine. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Plaquenil, Sovuna •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Hidroxicloroquina Hydroxychloroquine Hydroxychloroquinum Oxichlorochine Oxichloroquine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hydroxychloroquine is an antimalarial medication used to treat uncomplicated cases of malaria and for chemoprophylaxis in specific regions. Also a disease modifying anti-rheumatic drug (DMARD) indicated for treatment of rheumatoid arthritis and lupus erythematosus. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Hydroxyzine interact?

•Drug A: Buserelin •Drug B: Hydroxyzine •Severity: MAJOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Hydroxyzine. •Extended Description: Hydroxyzine is known to cause QTc interval prolongation1 and carries a "conditional" risk of Torsades de Pointes (TdP), meaning increased QT and TdP are only observed in patients with underlying risk factors or in cases of intentional overdose. Patient specific factors that increase the risk of QTc prolongation include pre-existing cardiovascular disease, low electrolyte levels (e.g. hypokalemia), endocrine disorders, and renal disease, amongst others. This risk is also significantly increased in patients receiving concomitant therapy with other medications known to prolong the QTc interval, such as the subject drug. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Hydroxyzine is indicated for the symptomatic relief of anxiety and tension associated with psychoneuroses, and as an adjunct in organic disease states in which anxiety is manifested. It is also indicated in the treatment of histamine-mediated pruritus and pruritus due to allergic conditions such as chronic urticaria. Canadian labeling states that hydroxyzine is also indicated in adults and children as a premedication prior to medical procedures, such as dental surgery. It is also used in the control of nausea and vomiting, excluding nausea and vomiting of pregnancy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hydroxyzine blocks the activity of histamine to relieve allergic symptoms such as pruritus. Activity at off-targets also allows for its use as a sedative anxiolytic and an antiemetic in certain disease states. Hydroxyzine is relatively fast-acting, with an onset of effect that occurs between 15 and 60 minutes and a duration of action between 4-6 hours. Hydroxyzine may potentiate the effects of central nervous system (CNS) depressants following general anesthesia - patients maintained on hydroxyzine should receive reduced doses of any CNS depressants required. Hydroxyzine is reported to prolong the QT/QTc interval based on postmarketing reports of rare events of Torsade de Pointes, cardiac arrest, and sudden death, and should be used with caution in patients with an increased baseline risk for QTc prolongation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The H 1 histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H 1 receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Hydroxyzine is a potent inverse agonist of histamine H 1 -receptors - inverse agonists are agents that are considered to have a "negative efficacy", so rather than simply blocking activity at a receptor they actively dampen its activity. Inverse agonism at these receptors is responsible for hydroxyzine's efficacy in the treatment of histaminic edema, flare, and pruritus. Hydroxyzine is not a cortical depressant, so its sedative properties likely occur at the subcortical level of the CNS. These sedative properties allow activity as an anxiolytic. Antiemetic efficacy is likely secondary to activity at off-targets. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (T max ) approximately 2 hours following administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): Hydroxyzine has been shown to bind to human albumin in vitro, but the extent of protein binding in plasma has not been evaluated. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine cetirizine. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life of hydroxyzine is reportedly 14-25 hours, and appears to be, on average, shorter in children (~7.1 hours) than in adults (~20 hours). Elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and is likely to be similarly prolonged in patients with renal or hepatic impairment. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 840 mg/kg in rats and 400 mg/kg in mice. Overdose from hydroxyzine is most commonly characterized by hypersedation, but may also manifest as convulsions, stupor, nausea, and vomiting. In cases of overdose, consider the induction of vomiting and the use of gastric lavage. Other treatment should involve general symptomatic and supportive care. Hypotension may be controlled by intravenous fluids and pressors, and caffeine and sodium benzoate injection may be used to counteract any observed CNS depressant effects. Hemodialysis is unlikely to provide any benefit in the treatment hydroxyzine overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Atarax, Vistaril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hydroxyzine is an antihistamine used to treat anxiety and tension associated with psychoneuroses, as well as allergic conditions such as pruritus and chronic urticaria.

Hydroxyzine is known to cause QTc interval prolongation1 and carries a "conditional" risk of Torsades de Pointes (TdP), meaning increased QT and TdP are only observed in patients with underlying risk factors or in cases of intentional overdose. Patient specific factors that increase the risk of QTc prolongation include pre-existing cardiovascular disease, low electrolyte levels (e.g. hypokalemia), endocrine disorders, and renal disease, amongst others. This risk is also significantly increased in patients receiving concomitant therapy with other medications known to prolong the QTc interval, such as the subject drug. The severity of the interaction is major.

Question: Does Buserelin and Hydroxyzine interact? Information: •Drug A: Buserelin •Drug B: Hydroxyzine •Severity: MAJOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Hydroxyzine. •Extended Description: Hydroxyzine is known to cause QTc interval prolongation1 and carries a "conditional" risk of Torsades de Pointes (TdP), meaning increased QT and TdP are only observed in patients with underlying risk factors or in cases of intentional overdose. Patient specific factors that increase the risk of QTc prolongation include pre-existing cardiovascular disease, low electrolyte levels (e.g. hypokalemia), endocrine disorders, and renal disease, amongst others. This risk is also significantly increased in patients receiving concomitant therapy with other medications known to prolong the QTc interval, such as the subject drug. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Hydroxyzine is indicated for the symptomatic relief of anxiety and tension associated with psychoneuroses, and as an adjunct in organic disease states in which anxiety is manifested. It is also indicated in the treatment of histamine-mediated pruritus and pruritus due to allergic conditions such as chronic urticaria. Canadian labeling states that hydroxyzine is also indicated in adults and children as a premedication prior to medical procedures, such as dental surgery. It is also used in the control of nausea and vomiting, excluding nausea and vomiting of pregnancy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hydroxyzine blocks the activity of histamine to relieve allergic symptoms such as pruritus. Activity at off-targets also allows for its use as a sedative anxiolytic and an antiemetic in certain disease states. Hydroxyzine is relatively fast-acting, with an onset of effect that occurs between 15 and 60 minutes and a duration of action between 4-6 hours. Hydroxyzine may potentiate the effects of central nervous system (CNS) depressants following general anesthesia - patients maintained on hydroxyzine should receive reduced doses of any CNS depressants required. Hydroxyzine is reported to prolong the QT/QTc interval based on postmarketing reports of rare events of Torsade de Pointes, cardiac arrest, and sudden death, and should be used with caution in patients with an increased baseline risk for QTc prolongation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The H 1 histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H 1 receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Hydroxyzine is a potent inverse agonist of histamine H 1 -receptors - inverse agonists are agents that are considered to have a "negative efficacy", so rather than simply blocking activity at a receptor they actively dampen its activity. Inverse agonism at these receptors is responsible for hydroxyzine's efficacy in the treatment of histaminic edema, flare, and pruritus. Hydroxyzine is not a cortical depressant, so its sedative properties likely occur at the subcortical level of the CNS. These sedative properties allow activity as an anxiolytic. Antiemetic efficacy is likely secondary to activity at off-targets. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (T max ) approximately 2 hours following administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): Hydroxyzine has been shown to bind to human albumin in vitro, but the extent of protein binding in plasma has not been evaluated. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine cetirizine. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life of hydroxyzine is reportedly 14-25 hours, and appears to be, on average, shorter in children (~7.1 hours) than in adults (~20 hours). Elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and is likely to be similarly prolonged in patients with renal or hepatic impairment. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 is 840 mg/kg in rats and 400 mg/kg in mice. Overdose from hydroxyzine is most commonly characterized by hypersedation, but may also manifest as convulsions, stupor, nausea, and vomiting. In cases of overdose, consider the induction of vomiting and the use of gastric lavage. Other treatment should involve general symptomatic and supportive care. Hypotension may be controlled by intravenous fluids and pressors, and caffeine and sodium benzoate injection may be used to counteract any observed CNS depressant effects. Hemodialysis is unlikely to provide any benefit in the treatment hydroxyzine overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Atarax, Vistaril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hydroxyzine is an antihistamine used to treat anxiety and tension associated with psychoneuroses, as well as allergic conditions such as pruritus and chronic urticaria. Output: Hydroxyzine is known to cause QTc interval prolongation1 and carries a "conditional" risk of Torsades de Pointes (TdP), meaning increased QT and TdP are only observed in patients with underlying risk factors or in cases of intentional overdose. Patient specific factors that increase the risk of QTc prolongation include pre-existing cardiovascular disease, low electrolyte levels (e.g. hypokalemia), endocrine disorders, and renal disease, amongst others. This risk is also significantly increased in patients receiving concomitant therapy with other medications known to prolong the QTc interval, such as the subject drug. The severity of the interaction is major.

Does Buserelin and Hyoscyamine interact?

•Drug A: Buserelin •Drug B: Hyoscyamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Hyoscyamine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As a drug that is not FDA approved, hyscyamine has no official indications. Intravenous hysocyamine has been used to reduce gastric motility, reduce pancreatic pain and secretions, to facilitate imaging of the gastrointestinal tract, treat anticholinesterase toxicity, treat certain cases of partial heart block, improve visualization of the kidneys, and for symptomatic relief of biliary and renal colic. Intravenous hyoscyamine is also used pre-operatively to reduce secretions of the mouth and respiratory tract to facilitate intubation. Oral hyoscyamine is used to treat functional intestinal disorders, for symptomatic relief of biliary and renal colic, and symptomatic relief of acute rhinitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hyoscyamine is not FDA approved, and so it has not official indications. However, it is used as an antimuscarinic agent in a number of treatments and therapies. Hyoscyamine has a short duration of action as it may need to be given multiple times per day. Patients should be counselled regarding the risks and signs of anticholinergic toxicity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Hyoscyamine competitively and non-selectively antagonises muscarinic receptors in the smooth muscle, cardiac muscle, sino-atrial node, atrioventricular node, exocrine nodes, gastrointestinal tract, and respiratory tract. Antagonism of muscarinic M1, M4, and M5 receptors in the central nervous system lead to cognitive impairment; antagonism of M2 in the sinoatrial and atrioventricular nodes leads to increases in heart rate and atrial contractility; and antagonism of M3 in smooth muscle results in reduced peristalsis, bladder contraction, salivary secretions, gastric secretions, bronchial secretions, sweating, increased bronchodilation, mydriasis, and cycloplegia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Hyoscyamine is completely absorbed by sublingual and oral routes, though exact data regarding the C max, T max, and AUC are not readily available. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hyoscyamine is largely unmetabolized, however a small amount is hydrolyzed into tropine and tropic acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The majority of hyoscyamine is eliminated in the urine as the unmetabolized parent compound. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of hyoscyamine is 3.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, nausea, vomiting, dizziness, dry mouth, difficulty in swallowing, dilated pupils, blurred vision, urinary retention, hot dry and flushed skin, tachycardia, hypertension, hypotension, respiratory depression, CNS stimulation, fever, ataxia, excitation, lethargy, stupor, coma, and paralysis. Patients should be treated with symptomatic and supportive therapy which may include emesis, gastric lavage, activated charcoal, artificial respiration, or intravenous physostigmine. Dialysis is expected to remove hyoscyamine sulfate from circulation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anaspaz, Donnatal, Ed Spaz, Hyophen, Levbid, Levsin, Nulev, Oscimin, Phenohytro, Phosphasal, Symax, Urelle, Uribel, Urimar Reformulated Oct 2013, Urin DS, Urogesic Blue Reformulated Apr 2012, Ustell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-atropine Daturin Daturine Duboisine Hyoscyamin Hyoscyamine Hyoscyaminum L-Hyoscyamine L-Tropine tropate Tropine-L-tropate •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hyoscyamine is an anticholinergic indicated to treat functional gastrointestinal disorders, biliary and renal colic, and acute rhinitis.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Hyoscyamine interact? Information: •Drug A: Buserelin •Drug B: Hyoscyamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Hyoscyamine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As a drug that is not FDA approved, hyscyamine has no official indications. Intravenous hysocyamine has been used to reduce gastric motility, reduce pancreatic pain and secretions, to facilitate imaging of the gastrointestinal tract, treat anticholinesterase toxicity, treat certain cases of partial heart block, improve visualization of the kidneys, and for symptomatic relief of biliary and renal colic. Intravenous hyoscyamine is also used pre-operatively to reduce secretions of the mouth and respiratory tract to facilitate intubation. Oral hyoscyamine is used to treat functional intestinal disorders, for symptomatic relief of biliary and renal colic, and symptomatic relief of acute rhinitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Hyoscyamine is not FDA approved, and so it has not official indications. However, it is used as an antimuscarinic agent in a number of treatments and therapies. Hyoscyamine has a short duration of action as it may need to be given multiple times per day. Patients should be counselled regarding the risks and signs of anticholinergic toxicity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Hyoscyamine competitively and non-selectively antagonises muscarinic receptors in the smooth muscle, cardiac muscle, sino-atrial node, atrioventricular node, exocrine nodes, gastrointestinal tract, and respiratory tract. Antagonism of muscarinic M1, M4, and M5 receptors in the central nervous system lead to cognitive impairment; antagonism of M2 in the sinoatrial and atrioventricular nodes leads to increases in heart rate and atrial contractility; and antagonism of M3 in smooth muscle results in reduced peristalsis, bladder contraction, salivary secretions, gastric secretions, bronchial secretions, sweating, increased bronchodilation, mydriasis, and cycloplegia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Hyoscyamine is completely absorbed by sublingual and oral routes, though exact data regarding the C max, T max, and AUC are not readily available. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hyoscyamine is largely unmetabolized, however a small amount is hydrolyzed into tropine and tropic acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The majority of hyoscyamine is eliminated in the urine as the unmetabolized parent compound. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of hyoscyamine is 3.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, nausea, vomiting, dizziness, dry mouth, difficulty in swallowing, dilated pupils, blurred vision, urinary retention, hot dry and flushed skin, tachycardia, hypertension, hypotension, respiratory depression, CNS stimulation, fever, ataxia, excitation, lethargy, stupor, coma, and paralysis. Patients should be treated with symptomatic and supportive therapy which may include emesis, gastric lavage, activated charcoal, artificial respiration, or intravenous physostigmine. Dialysis is expected to remove hyoscyamine sulfate from circulation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anaspaz, Donnatal, Ed Spaz, Hyophen, Levbid, Levsin, Nulev, Oscimin, Phenohytro, Phosphasal, Symax, Urelle, Uribel, Urimar Reformulated Oct 2013, Urin DS, Urogesic Blue Reformulated Apr 2012, Ustell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-atropine Daturin Daturine Duboisine Hyoscyamin Hyoscyamine Hyoscyaminum L-Hyoscyamine L-Tropine tropate Tropine-L-tropate •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Hyoscyamine is an anticholinergic indicated to treat functional gastrointestinal disorders, biliary and renal colic, and acute rhinitis. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ibandronate interact?

•Drug A: Buserelin •Drug B: Ibandronate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ibandronate is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment and prevention of osteoporosis in postmenopausal women. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ibandronate is a nitrogen containing bisphosphonate used to treat and prevent osteoporosis in postmenopausal women. The therapeutic index is wide as overdoses are not especially toxic, and the duration of action is long as the half life can be up to 157 hours. Patients should be counselled regarding the risk of upper GI adverse reactions, hypocalcemia, musculoskeletal pain, osteonecrosis of the jaw, atypical fractures of the femur, and severe renal impairment. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as ibandronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. ibandronate also activated caspase-3 which contribute to apoptosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral ibandronate is 0.63% bioavailable. In a study of healthy males, a 10mg oral dose had a T max of 1.1±0.6h and a C max of 4.1±2.6ng/mL. The T max is approximately 1 hour, while C max varies depending on dose. A 2mg intravenous dose of ibandronate has an AUC of 316ng*h/mL, a 4mg intravenous dose of ibandronate has an AUC of 581ng*h/mL, and a 6mg intravenous dose of ibandronate has an AUC of 908ng*h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent terminal volume of distribution of ibandronate is 90-368L in headlthy subjects and 103L in postmenopausal women with osteopenia. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ibandronate's protein binding in serum varies from 85.7-99.5% over a concentration of 0.5-10ng/mL, but is generally 86% across a concentration range of 20-2000ng/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ibanronate is not metabolized in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Ibandronate is predominantly eliminated in the urine and the unabsorbed drug is eliminated unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of ibandronate in postmenopausal women ranges from 37-157 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total clearance of ibandronate is 84-160mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with hypocalcemia, hypophosphatemia, upset stomach, dyspepsia, esophagitis, and uclers. Oral overdose can be managed by giving patients milk or antacids to bind excess unabsorbed ibandronate. Overdoses can be managed by providing intravenous electrolytes and dialysis is not expected to remove excess drug from serum. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bondronat, Boniva, Bonviva, Iasibon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ibandronate is a bisphosphonate used to treat osteoporosis in postmenopausal women.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ibandronate interact? Information: •Drug A: Buserelin •Drug B: Ibandronate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ibandronate is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment and prevention of osteoporosis in postmenopausal women. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ibandronate is a nitrogen containing bisphosphonate used to treat and prevent osteoporosis in postmenopausal women. The therapeutic index is wide as overdoses are not especially toxic, and the duration of action is long as the half life can be up to 157 hours. Patients should be counselled regarding the risk of upper GI adverse reactions, hypocalcemia, musculoskeletal pain, osteonecrosis of the jaw, atypical fractures of the femur, and severe renal impairment. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as ibandronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. ibandronate also activated caspase-3 which contribute to apoptosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral ibandronate is 0.63% bioavailable. In a study of healthy males, a 10mg oral dose had a T max of 1.1±0.6h and a C max of 4.1±2.6ng/mL. The T max is approximately 1 hour, while C max varies depending on dose. A 2mg intravenous dose of ibandronate has an AUC of 316ng*h/mL, a 4mg intravenous dose of ibandronate has an AUC of 581ng*h/mL, and a 6mg intravenous dose of ibandronate has an AUC of 908ng*h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent terminal volume of distribution of ibandronate is 90-368L in headlthy subjects and 103L in postmenopausal women with osteopenia. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ibandronate's protein binding in serum varies from 85.7-99.5% over a concentration of 0.5-10ng/mL, but is generally 86% across a concentration range of 20-2000ng/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ibanronate is not metabolized in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Ibandronate is predominantly eliminated in the urine and the unabsorbed drug is eliminated unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of ibandronate in postmenopausal women ranges from 37-157 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total clearance of ibandronate is 84-160mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with hypocalcemia, hypophosphatemia, upset stomach, dyspepsia, esophagitis, and uclers. Oral overdose can be managed by giving patients milk or antacids to bind excess unabsorbed ibandronate. Overdoses can be managed by providing intravenous electrolytes and dialysis is not expected to remove excess drug from serum. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bondronat, Boniva, Bonviva, Iasibon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ibandronate is a bisphosphonate used to treat osteoporosis in postmenopausal women. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ibutilide interact?

•Drug A: Buserelin •Drug B: Ibutilide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ibutilide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ibutilide prolongs the action potential duration and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca channel blockers and potent inhibition of the cardiac rapid delayed rectifier K current, by binding within potassium channel pores. In other words, Ibutilide binds to and alters the activity of hERG potassium channels, delayed inward rectifier potassium (IKr) channels and L-type (dihydropyridine sensitive) calcium channels •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapid after intravenous injection •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 11 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 40% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic. Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by o-oxidation followed by sequential b-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the o-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 6 hours (ranges from 2-12 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): 29 mL/min/kg •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m basis, at least 250 times the maximum recommended human dose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Corvert •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ibutilid Ibutilida Ibutilide Ibutilidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ibutilide is a class III antiarrhythmic agent used to correct atrial fibrillation and atrial flutter, which can be considered as an alternative to cardioversion.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Ibutilide interact? Information: •Drug A: Buserelin •Drug B: Ibutilide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ibutilide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ibutilide prolongs the action potential duration and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca channel blockers and potent inhibition of the cardiac rapid delayed rectifier K current, by binding within potassium channel pores. In other words, Ibutilide binds to and alters the activity of hERG potassium channels, delayed inward rectifier potassium (IKr) channels and L-type (dihydropyridine sensitive) calcium channels •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapid after intravenous injection •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 11 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 40% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic. Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by o-oxidation followed by sequential b-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the o-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 6 hours (ranges from 2-12 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): 29 mL/min/kg •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m basis, at least 250 times the maximum recommended human dose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Corvert •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ibutilid Ibutilida Ibutilide Ibutilidum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ibutilide is a class III antiarrhythmic agent used to correct atrial fibrillation and atrial flutter, which can be considered as an alternative to cardioversion. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Iloperidone interact?

•Drug A: Buserelin •Drug B: Iloperidone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Iloperidone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Treatment of acute schizophrenia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Apparent Vd = 1340-2800 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal (in which <1% of iloperidone is excreted unchanged). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent clearance (clearance/bioavilability) = 47-102 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Commonly observed adverse reactions (incidence ≥5% and two-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Fanapt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Iloperidona Iloperidone Ilopéridone Iloperidonum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Iloperidone is an atypical antipsychotic agent used for the acute treatment of schizophrenia in adults.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Iloperidone interact? Information: •Drug A: Buserelin •Drug B: Iloperidone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Iloperidone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Treatment of acute schizophrenia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Apparent Vd = 1340-2800 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal (in which <1% of iloperidone is excreted unchanged). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent clearance (clearance/bioavilability) = 47-102 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Commonly observed adverse reactions (incidence ≥5% and two-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Fanapt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Iloperidona Iloperidone Ilopéridone Iloperidonum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Iloperidone is an atypical antipsychotic agent used for the acute treatment of schizophrenia in adults. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Imatinib interact?

•Drug A: Buserelin •Drug B: Imatinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Imatinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Imatinib is indicated for the treatment of adult and pediatric chronic myeloid leukemia with Philadelphia chromosome mutation (Ph+) in blast crisis, accelerated phase, or chronic phase after IFN-alpha therapy failure. Additionally, imatinib is also indicated to treat adult and pediatric Ph+ acute lymphoblastic leukemia, adult myelodysplastic/myeloproliferative diseases, adult aggressive systemic mastocytosis, adult hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), adult dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Imatinib is a 2-phenylaminopyrimidine derivative neoplastic agent that belongs to the class of tyrosine kinase inhibitors. Although imatinib inhibits a number of tyrosine kinases, it is quite selective toward the BCR-ABL fusion protein that is present in various cancers. BCR-ABL pathway controls many downstream pathways that are heavily implicated in neoplastic growth such as the Ras/MapK pathway (cellular proliferation), Src/Pax/Fak/Rac pathway (cellular motility), and PI/PI3K/AKT/BCL-2 pathway (apoptosis pathway). Therefore, the BCR-ABL pathway is an attractive target for cancer treatment. Although normal cells also depend on these pathways for growth, these cells tend to have redundant tyrosine kinases to continually function in spite of ABL inhibition from imatinib. Cancer cells, on the other hand, can have a dependence on BCR-ABL, thus more heavily impacted by imatinib. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutively active tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Although the function of normal BCR is still unclear, ABL activation is overexpressed in various tumors and is heavily implicated in cancer cells growth and survival. Imatinib inhibits the BCR-ABL protein by binding to the ATP pocket in the active site, thus preventing downstream phosphorylation of target protein. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at a steady state when Gleevec is dosed once daily. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Population pharmacokinetics in adult CML patients estimated the steady-state volume of distribution of imatinib to be 295.0 ± 62.5 L. At a dose of 340 mg/m, the volume of distribution of imatinib in pediatric patients was calculated to be 167 ± 84 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 is the major enzyme responsible for the metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicities. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at greater than or equal to 30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach. Neoplastic lesions were not seen at 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland was noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on BSA. This was not seen at doses less than or equal to 20 mg/kg (one-fourth of the maximum human dose of 800 mg). The fertility of male and female rats was not affected. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights, as well as a reduced number of motile sperm, were observed in the high-dose male rats. In the preclinical pre-and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib mesylate. It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in the worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died in the study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females), and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study that were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Gleevec, Glivec •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imatinib Imatinibum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Imatinib is a tyrosine kinase inhibitor used to treat a number of leukemias, myelodysplastic/myeloproliferative disease, systemic mastocytosis, hypereosinophilic syndrome, dermatofibrosarcoma protuberans, and gastrointestinal stromal tumors.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Imatinib interact? Information: •Drug A: Buserelin •Drug B: Imatinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Imatinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Imatinib is indicated for the treatment of adult and pediatric chronic myeloid leukemia with Philadelphia chromosome mutation (Ph+) in blast crisis, accelerated phase, or chronic phase after IFN-alpha therapy failure. Additionally, imatinib is also indicated to treat adult and pediatric Ph+ acute lymphoblastic leukemia, adult myelodysplastic/myeloproliferative diseases, adult aggressive systemic mastocytosis, adult hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), adult dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Imatinib is a 2-phenylaminopyrimidine derivative neoplastic agent that belongs to the class of tyrosine kinase inhibitors. Although imatinib inhibits a number of tyrosine kinases, it is quite selective toward the BCR-ABL fusion protein that is present in various cancers. BCR-ABL pathway controls many downstream pathways that are heavily implicated in neoplastic growth such as the Ras/MapK pathway (cellular proliferation), Src/Pax/Fak/Rac pathway (cellular motility), and PI/PI3K/AKT/BCL-2 pathway (apoptosis pathway). Therefore, the BCR-ABL pathway is an attractive target for cancer treatment. Although normal cells also depend on these pathways for growth, these cells tend to have redundant tyrosine kinases to continually function in spite of ABL inhibition from imatinib. Cancer cells, on the other hand, can have a dependence on BCR-ABL, thus more heavily impacted by imatinib. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutively active tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Although the function of normal BCR is still unclear, ABL activation is overexpressed in various tumors and is heavily implicated in cancer cells growth and survival. Imatinib inhibits the BCR-ABL protein by binding to the ATP pocket in the active site, thus preventing downstream phosphorylation of target protein. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at a steady state when Gleevec is dosed once daily. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Population pharmacokinetics in adult CML patients estimated the steady-state volume of distribution of imatinib to be 295.0 ± 62.5 L. At a dose of 340 mg/m, the volume of distribution of imatinib in pediatric patients was calculated to be 167 ± 84 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 is the major enzyme responsible for the metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicities. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at greater than or equal to 30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach. Neoplastic lesions were not seen at 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland was noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on BSA. This was not seen at doses less than or equal to 20 mg/kg (one-fourth of the maximum human dose of 800 mg). The fertility of male and female rats was not affected. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights, as well as a reduced number of motile sperm, were observed in the high-dose male rats. In the preclinical pre-and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib mesylate. It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in the worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died in the study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females), and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study that were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Gleevec, Glivec •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imatinib Imatinibum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Imatinib is a tyrosine kinase inhibitor used to treat a number of leukemias, myelodysplastic/myeloproliferative disease, systemic mastocytosis, hypereosinophilic syndrome, dermatofibrosarcoma protuberans, and gastrointestinal stromal tumors. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Imipramine interact?

•Drug A: Buserelin •Drug B: Imipramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Imipramine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation. •Protein binding (Drug A): 15% •Protein binding (Drug B): Imipramine is 60-96% bound to plasma proteins in circulation. It is known to bind albumin, α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Imipramine is primarily excreted in the urine with less than 5% present as the parent compound •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations. Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue. Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured. Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention. Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs. LD 50 Values Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg Human range of toxicity is considered to include single dosages greater than 5 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tofranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imipramin Imipramina Imipramine Imipraminum Imizine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Imipramine interact? Information: •Drug A: Buserelin •Drug B: Imipramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Imipramine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation. •Protein binding (Drug A): 15% •Protein binding (Drug B): Imipramine is 60-96% bound to plasma proteins in circulation. It is known to bind albumin, α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Imipramine is primarily excreted in the urine with less than 5% present as the parent compound •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations. Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue. Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured. Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention. Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs. LD 50 Values Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg Human range of toxicity is considered to include single dosages greater than 5 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tofranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imipramin Imipramina Imipramine Imipraminum Imizine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Indacaterol interact?

•Drug A: Buserelin •Drug B: Indacaterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Indacaterol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the long term, once-daily-dosing maintenance of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359] •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes. The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): After oral administration of radiolabeled indacaterol, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. The monohydroxylated derivative, glucuronide conjugate, and the 8-O-glucuronide were the most prominent metabolites in serum. Other metabolites identified include a diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products. In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. CYP3A4 is the predominant isoenzyme responsible for hydroxylation of indacaterol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance of indacaterol is, on average, between 0.46 and 1.2 L/h. Serum clearance of indacaterol is 18.8 L/h to 23.3 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The expected signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Hirobriz, Onbrez, Ultibro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Indacaterol is an inhaled long-acting beta-2 adrenergic agonist used to relax bronchial smooth muscle and improve symptoms and airflow obstruction caused by Chronic Obstructive Pulmonary Disease (COPD) and moderate to severe asthma.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Indacaterol interact? Information: •Drug A: Buserelin •Drug B: Indacaterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Indacaterol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the long term, once-daily-dosing maintenance of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359] •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes. The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): After oral administration of radiolabeled indacaterol, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. The monohydroxylated derivative, glucuronide conjugate, and the 8-O-glucuronide were the most prominent metabolites in serum. Other metabolites identified include a diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products. In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. CYP3A4 is the predominant isoenzyme responsible for hydroxylation of indacaterol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance of indacaterol is, on average, between 0.46 and 1.2 L/h. Serum clearance of indacaterol is 18.8 L/h to 23.3 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The expected signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Hirobriz, Onbrez, Ultibro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Indacaterol is an inhaled long-acting beta-2 adrenergic agonist used to relax bronchial smooth muscle and improve symptoms and airflow obstruction caused by Chronic Obstructive Pulmonary Disease (COPD) and moderate to severe asthma. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Indapamide interact?

•Drug A: Buserelin •Drug B: Indapamide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Indapamide is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indapamide is a diuretic indicated for use as monotherapy or in combination with other blood pressure-lowering agents to treat hypertension. It may also be used to treat fluid and salt retention associated with congestive heart failure. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium. Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure. Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes. Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC 0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 76-79% of indapamide is protein bound. Indapamide binds primarily to alpha 1-acid glycoprotein and less significantly to serum albumin and lipoproteins. In the blood, indapamide is extensively and preferentially bound to erythrocytes. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): As a result of extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged. In humans, as many as 19 distinct indapamide metabolites may be produced, although not all have been identified. There are several metabolic routes through which indapamide may be metabolized, and CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions. Indapamide can undergo dehydrogenation to form M5, then oxidation to form M4, then further hydroxylation at the indole moiety to form M2. These reactions are facilitated by CYP3A4. Another route of metabolism occurs when indapamide is first hydroxylated to M1 by CYP3A4. M1 then undergoes dehydrogenation to form M3 and is further oxidized to form M2. Hydroxylation of indapamide’s indole moiety is thought to form the major metabolite (M1), which is less pharmacologically active compared to its parent compound according to animal studies. Indapamide may also undergo epoxidation via CYP3A4 to form a reactive epoxide intermediate. The unstable epoxide intermediate may then undergo dihydroxylation via microsomal epoxide hydrolase to form M6, or glutathione conjugation to form M7. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Indapamide is characterized by biphasic elimination. In healthy subjects, indapamide's elimination half-life can range from 13.9 to 18 hours. The long half-life is conducive to once-daily dosing. •Clearance (Drug A): No clearance available •Clearance (Drug B): Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Coversyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Indapamide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Indapamide interact? Information: •Drug A: Buserelin •Drug B: Indapamide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Indapamide is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indapamide is a diuretic indicated for use as monotherapy or in combination with other blood pressure-lowering agents to treat hypertension. It may also be used to treat fluid and salt retention associated with congestive heart failure. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium. Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure. Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes. Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC 0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 76-79% of indapamide is protein bound. Indapamide binds primarily to alpha 1-acid glycoprotein and less significantly to serum albumin and lipoproteins. In the blood, indapamide is extensively and preferentially bound to erythrocytes. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): As a result of extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged. In humans, as many as 19 distinct indapamide metabolites may be produced, although not all have been identified. There are several metabolic routes through which indapamide may be metabolized, and CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions. Indapamide can undergo dehydrogenation to form M5, then oxidation to form M4, then further hydroxylation at the indole moiety to form M2. These reactions are facilitated by CYP3A4. Another route of metabolism occurs when indapamide is first hydroxylated to M1 by CYP3A4. M1 then undergoes dehydrogenation to form M3 and is further oxidized to form M2. Hydroxylation of indapamide’s indole moiety is thought to form the major metabolite (M1), which is less pharmacologically active compared to its parent compound according to animal studies. Indapamide may also undergo epoxidation via CYP3A4 to form a reactive epoxide intermediate. The unstable epoxide intermediate may then undergo dihydroxylation via microsomal epoxide hydrolase to form M6, or glutathione conjugation to form M7. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Indapamide is characterized by biphasic elimination. In healthy subjects, indapamide's elimination half-life can range from 13.9 to 18 hours. The long half-life is conducive to once-daily dosing. •Clearance (Drug A): No clearance available •Clearance (Drug B): Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Coversyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Indapamide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Inotersen interact?

•Drug A: Buserelin •Drug B: Inotersen •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Inotersen. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Protein binding (Drug A): 15% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Clearance (Drug A): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Brand Names (Drug A): Suprefact •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Summary not found

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Inotersen interact? Information: •Drug A: Buserelin •Drug B: Inotersen •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Inotersen. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Protein binding (Drug A): 15% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Clearance (Drug A): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Brand Names (Drug A): Suprefact •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Summary not found Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Insulin aspart interact?

•Drug A: Buserelin •Drug B: Insulin aspart •Severity: MODERATE •Description: The therapeutic efficacy of Insulin aspart can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin aspart is indicated to improve glycemic control in adults and children with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin aspart is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin aspart is 10-15 minutes. Its activity peaks 60-90 minutes following subcutaneous injection and its duration of action is 4-5 hours. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin aspart binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the proline residue at B28 with aspartic acid reduces the tendency to form hexamers and results in a faster rate of absorption and onset of action and shorter duration of action. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In studies of healthy volunteers and patients with type 1 diabetes, the median time to maximum concentration of insulin aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. Compared to human insulin, insulin aspart has a faster absorption, a faster onset of action, and a shorter duration of action than regular human insulin after subcutaneous injection. It takes 40 - 50 minutes to reach maximum concentration. When a dose of 0.15 U/kg body weight was injected in type 1 diabetes patients, the mean maximum concentration (Cmax) was 82 mU/L. The site of injection has no impact on extent or speed of absorption. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elimination half-life was found to be 81 minutes (following subcutaneous administration in healthy subjects). •Clearance (Drug A): No clearance available •Clearance (Drug B): 1.2 L/h/kg •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Fiasp, Novolog, Novolog Mix, Novomix, Novorapid, Novorapid Penfill, Ryzodeg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin aspart is a rapid-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin aspart interact? Information: •Drug A: Buserelin •Drug B: Insulin aspart •Severity: MODERATE •Description: The therapeutic efficacy of Insulin aspart can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin aspart is indicated to improve glycemic control in adults and children with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin aspart is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin aspart is 10-15 minutes. Its activity peaks 60-90 minutes following subcutaneous injection and its duration of action is 4-5 hours. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin aspart binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the proline residue at B28 with aspartic acid reduces the tendency to form hexamers and results in a faster rate of absorption and onset of action and shorter duration of action. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In studies of healthy volunteers and patients with type 1 diabetes, the median time to maximum concentration of insulin aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. Compared to human insulin, insulin aspart has a faster absorption, a faster onset of action, and a shorter duration of action than regular human insulin after subcutaneous injection. It takes 40 - 50 minutes to reach maximum concentration. When a dose of 0.15 U/kg body weight was injected in type 1 diabetes patients, the mean maximum concentration (Cmax) was 82 mU/L. The site of injection has no impact on extent or speed of absorption. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elimination half-life was found to be 81 minutes (following subcutaneous administration in healthy subjects). •Clearance (Drug A): No clearance available •Clearance (Drug B): 1.2 L/h/kg •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Fiasp, Novolog, Novolog Mix, Novomix, Novorapid, Novorapid Penfill, Ryzodeg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin aspart is a rapid-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin degludec interact?

•Drug A: Buserelin •Drug B: Insulin degludec •Severity: MODERATE •Description: The therapeutic efficacy of Insulin degludec can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In nondiabetic individuals, the pancreas produces a continuous supply of low basal insulin levels and spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to an absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It mimics the basal insulin levels in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc, and Gab 1. Activation of these proteins leads to activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In patients with type 1 diabetes, after 8 days of once-daily subcutaneous dosing with 0.4 U/kg, maximum insulin degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (t max ). After the first dose, the median onset of appearance was around one hour. The glucose-lowering effect lasted at least 42 hours after the last of 8 once-daily injections. Insulin degludec concentration reaches steady-state levels after 3-4 days. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Using a one-compartment pharmacokinetics model, the apparent volume of distribution was estimated to be 10.6 L for the pediatric population and 13.9 L for the adult population. •Protein binding (Drug A): 15% •Protein binding (Drug B): The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma. The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein-bound drugs. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): All insulin degludec metabolites are inactive. The liver and kidney play the major role in metabolizing insulin. However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 30 to 80% of circulating insulin is removed by the kidney. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at a steady state is approximately 25 hours independent of dose. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individuals) after a single subcutaneous dose of 0.4 units/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can usually be treated with oral glucose. Lowering the insulin dosage and adjusting meal patterns or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid the reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately. Insulin degludec was investigated in studies covering fertility, embryo-fetal development, and pre and post-natal development in rats and during the period of embryo-fetal development in rabbits. Human insulin (NPH insulin) was included as a comparator. In these studies, insulin degludec caused pre and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which was probably secondary to maternal hypoglycemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ryzodeg, Tresiba, Xultophy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin degludec is a long acting insulin used to treat hyperglycemia caused by type 1 and 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin degludec interact? Information: •Drug A: Buserelin •Drug B: Insulin degludec •Severity: MODERATE •Description: The therapeutic efficacy of Insulin degludec can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In nondiabetic individuals, the pancreas produces a continuous supply of low basal insulin levels and spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to an absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It mimics the basal insulin levels in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc, and Gab 1. Activation of these proteins leads to activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In patients with type 1 diabetes, after 8 days of once-daily subcutaneous dosing with 0.4 U/kg, maximum insulin degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (t max ). After the first dose, the median onset of appearance was around one hour. The glucose-lowering effect lasted at least 42 hours after the last of 8 once-daily injections. Insulin degludec concentration reaches steady-state levels after 3-4 days. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Using a one-compartment pharmacokinetics model, the apparent volume of distribution was estimated to be 10.6 L for the pediatric population and 13.9 L for the adult population. •Protein binding (Drug A): 15% •Protein binding (Drug B): The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma. The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein-bound drugs. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): All insulin degludec metabolites are inactive. The liver and kidney play the major role in metabolizing insulin. However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 30 to 80% of circulating insulin is removed by the kidney. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at a steady state is approximately 25 hours independent of dose. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individuals) after a single subcutaneous dose of 0.4 units/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can usually be treated with oral glucose. Lowering the insulin dosage and adjusting meal patterns or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid the reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately. Insulin degludec was investigated in studies covering fertility, embryo-fetal development, and pre and post-natal development in rats and during the period of embryo-fetal development in rabbits. Human insulin (NPH insulin) was included as a comparator. In these studies, insulin degludec caused pre and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which was probably secondary to maternal hypoglycemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ryzodeg, Tresiba, Xultophy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin degludec is a long acting insulin used to treat hyperglycemia caused by type 1 and 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin detemir interact?

•Drug A: Buserelin •Drug B: Insulin detemir •Severity: MODERATE •Description: The therapeutic efficacy of Insulin detemir can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin detemir is indicated to improve glycemic control in adults and children with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signalling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. Insulin detemir’s long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slow its distribution into target tissues and prolong its duration of action. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post dose. When single dose of 0.5 units/kg of insulin detemir was given to adult type 1 diabetes patients, the maximum serum concentration (Cmax) was 4,641 ± 2,299 pmol/L. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC 0-5h was 30 40% lower and AUC 0-∞ was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. Insulin detemir has a slow and prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak. The median time to maximum serum insulin concentration was 12 hours after injection. On average, serum insulin concentrations declined to baseline by approximately 24 hours. The absolute bioavailability of insulin detemir is approximately 60%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The liver and kidney play the major role in metabolizing insulin. However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 30 to 80% of circulating insulin is removed by the kidney. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours depending on dose. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance (CL/F) was fairly consistent among different patients population with type 1 diabetes. It was estimated to be 3.43 ± 1.36 L/min·kg in 6 to 12 years old patients, 3.74 ± 0.98 L/min·kg in 13 to 17 years old, and 3.41 ± 1.00 L/min·kg in adult patients (18-65 years old). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Individuals may become unconscious in severe cases of hypoglycemia. Injection site reactions may also occur. Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Levemir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin detemir is a long-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin detemir interact? Information: •Drug A: Buserelin •Drug B: Insulin detemir •Severity: MODERATE •Description: The therapeutic efficacy of Insulin detemir can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin detemir is indicated to improve glycemic control in adults and children with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signalling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. Insulin detemir’s long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slow its distribution into target tissues and prolong its duration of action. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post dose. When single dose of 0.5 units/kg of insulin detemir was given to adult type 1 diabetes patients, the maximum serum concentration (Cmax) was 4,641 ± 2,299 pmol/L. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC 0-5h was 30 40% lower and AUC 0-∞ was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. Insulin detemir has a slow and prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak. The median time to maximum serum insulin concentration was 12 hours after injection. On average, serum insulin concentrations declined to baseline by approximately 24 hours. The absolute bioavailability of insulin detemir is approximately 60%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The liver and kidney play the major role in metabolizing insulin. However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 30 to 80% of circulating insulin is removed by the kidney. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours depending on dose. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance (CL/F) was fairly consistent among different patients population with type 1 diabetes. It was estimated to be 3.43 ± 1.36 L/min·kg in 6 to 12 years old patients, 3.74 ± 0.98 L/min·kg in 13 to 17 years old, and 3.41 ± 1.00 L/min·kg in adult patients (18-65 years old). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Individuals may become unconscious in severe cases of hypoglycemia. Injection site reactions may also occur. Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Levemir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin detemir is a long-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin glargine interact?

•Drug A: Buserelin •Drug B: Insulin glargine •Severity: MODERATE •Description: The therapeutic efficacy of Insulin glargine can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin glargine is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin glargine is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin glargine binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signalling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism. Insulin glargine is completely soluble at pH 4, the pH of administered solution, and has low solubility at physiological pH 7.4. Upon subcuteous injection, the solution is neutralized resulting in the formation of microprecipitates. Small amounts of insulin glargine are released from microprecipitates giving the drug a relatively constant concentration over time profile over 24 hours with no pronounced peak. This release mechanism allows the drug to mimic basal insulin levels within the body. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Because of the modifications to the A and B chain, the isoelectric point shifts towards a neutral pH and insulin glargine is more stable in acidic conditions than regular insulin. As insulin glargine is less soluble at neutral pH, once injected, forms microprecipitates. Slow release of insulin glargine from microprecipitates provides a relatively constant concentration of insulin over 24 hours. Onset of action is approximately 1.1 hours. The pharmacokinetic profiles for single 0.4, 0.6, and 0.9 U/kg doses of Toujeo in 24 patients with type 1 diabetes mellitus was evaluated in a euglycemic clamp study. The median time to maximum serum insulin concentration was 12 (8–14), 12 (12–18), and 16 (12–20) hours, respectively. Steady-state insulin concentrations are reached by at least 5 days of once-daily subcutaneous administration of 0.4 U/kg to 0.6 U/kg doses of Toujeo over 8 days in patients with type 1 diabetes mellitus. The median time to maximum effect of Basaglar (measured by the peak rate of glucose infusion) was approximately 12.0 hours. The pharmacodynamic profile of Basaglar following subcutaneous injection demonstrated sustained glucose lowering activity over 24 hours with no pronounced peak. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) and maximum glucose infusion rate were 1670 mg/kg and 2.12 mg/kg/min, respectively. On average, serum insulin concentrations declined to baseline by approximately 24 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Insulin glargine is metabolized in the liver into two active metabolites with similar activity to insulin: 21a-Gly-human insulin (M1) and 21a-Gly-des-30b- threonine insulin (M2), with M1 being the predominant metabolite. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Other adverse events that may occur include allergic reaction, injection site reaction, lipodystrophy, pruritis, and rash. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Basaglar, Lantus, Rezvoglar, Semglee, Soliqua, Toujeo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin glargine is a modified form of long-acting or basal insulin used to control hyperglycemia in diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin glargine interact? Information: •Drug A: Buserelin •Drug B: Insulin glargine •Severity: MODERATE •Description: The therapeutic efficacy of Insulin glargine can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin glargine is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin glargine is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin glargine binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signalling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism. Insulin glargine is completely soluble at pH 4, the pH of administered solution, and has low solubility at physiological pH 7.4. Upon subcuteous injection, the solution is neutralized resulting in the formation of microprecipitates. Small amounts of insulin glargine are released from microprecipitates giving the drug a relatively constant concentration over time profile over 24 hours with no pronounced peak. This release mechanism allows the drug to mimic basal insulin levels within the body. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Because of the modifications to the A and B chain, the isoelectric point shifts towards a neutral pH and insulin glargine is more stable in acidic conditions than regular insulin. As insulin glargine is less soluble at neutral pH, once injected, forms microprecipitates. Slow release of insulin glargine from microprecipitates provides a relatively constant concentration of insulin over 24 hours. Onset of action is approximately 1.1 hours. The pharmacokinetic profiles for single 0.4, 0.6, and 0.9 U/kg doses of Toujeo in 24 patients with type 1 diabetes mellitus was evaluated in a euglycemic clamp study. The median time to maximum serum insulin concentration was 12 (8–14), 12 (12–18), and 16 (12–20) hours, respectively. Steady-state insulin concentrations are reached by at least 5 days of once-daily subcutaneous administration of 0.4 U/kg to 0.6 U/kg doses of Toujeo over 8 days in patients with type 1 diabetes mellitus. The median time to maximum effect of Basaglar (measured by the peak rate of glucose infusion) was approximately 12.0 hours. The pharmacodynamic profile of Basaglar following subcutaneous injection demonstrated sustained glucose lowering activity over 24 hours with no pronounced peak. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) and maximum glucose infusion rate were 1670 mg/kg and 2.12 mg/kg/min, respectively. On average, serum insulin concentrations declined to baseline by approximately 24 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Insulin glargine is metabolized in the liver into two active metabolites with similar activity to insulin: 21a-Gly-human insulin (M1) and 21a-Gly-des-30b- threonine insulin (M2), with M1 being the predominant metabolite. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Other adverse events that may occur include allergic reaction, injection site reaction, lipodystrophy, pruritis, and rash. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Basaglar, Lantus, Rezvoglar, Semglee, Soliqua, Toujeo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin glargine is a modified form of long-acting or basal insulin used to control hyperglycemia in diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin glulisine interact?

•Drug A: Buserelin •Drug B: Insulin glulisine •Severity: MODERATE •Description: The therapeutic efficacy of Insulin glulisine can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin glulisine is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin glulisine is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin glulisine is approximately 15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 2-4 hours. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin glulisine binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the arginine at position B3 for lysine and replacement of the B29 lysine with glutamic acid decreases the propensity to form hexamers, stabilizes the hormone in monomeric form and results in a rapid rate of absorption and short duration of action. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120 minutes) and the peak concentration (Cmax) was 83 microunits/mL (range 40 to 131 microunits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239 minutes) and a Cmax of 50 microunits/mL (range 35 to 71 microunits/mL) for regular human insulin. When insulin glulisine was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 13 L •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elimination half life= 42 minutes (following subcutaneous injection) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Apidra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin glulisine is a short-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin glulisine interact? Information: •Drug A: Buserelin •Drug B: Insulin glulisine •Severity: MODERATE •Description: The therapeutic efficacy of Insulin glulisine can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin glulisine is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin glulisine is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin glulisine is approximately 15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 2-4 hours. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin glulisine binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the arginine at position B3 for lysine and replacement of the B29 lysine with glutamic acid decreases the propensity to form hexamers, stabilizes the hormone in monomeric form and results in a rapid rate of absorption and short duration of action. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120 minutes) and the peak concentration (Cmax) was 83 microunits/mL (range 40 to 131 microunits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239 minutes) and a Cmax of 50 microunits/mL (range 35 to 71 microunits/mL) for regular human insulin. When insulin glulisine was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 13 L •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elimination half life= 42 minutes (following subcutaneous injection) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Apidra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin glulisine is a short-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin human interact?

•Drug A: Buserelin •Drug B: Insulin human •Severity: MODERATE •Description: The therapeutic efficacy of Insulin human can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Human insulin is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The primary activity of insulin is the regulation of glucose metabolism. Insulin promotes glucose and amino acid uptake into muscle and adipose tissues, and other tissues except brain and liver. It also has an anabolic role in stimulating glycogen, fatty acid, and protein synthesis. Insulin inhibits gluconeogenesis in the liver. Insulin binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC) which play a critical role in metabolism and catabolism. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): When injected subcutaneously, the glucose-lowering effect of human insulin begins approximately 30 minutes post-dose. After a single subcutaneous administration of 0.1 unit/kg of human insulin to healthy subjects, peak insulin concentrations occurred between 1.5 to 2.5 hours post-dose. When administered in an inhaled form (as the product Afrezza), the time to maximum serum insulin concentration ranges from 10-20 minutes after oral inhalation of 4 to 48 units of human insulin. Serum insulin concentrations declined to baseline by approximately 60-240 minutes for these dose levels. Intrapatient variability in insulin exposure measured by AUC and Cmax is approximately 16% (95% CI 12-23%) and 21% (95% CI 16-30%), respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolism and elimination of orally inhaled human insulin are comparable to regular human insulin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral inhalation of human insulin, a mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Systemic insulin disposition (apparent terminal half-life) following oral inhalation of 4 to 48 units of human insulin was 120-206 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actraphane, Actrapid, Afrezza, Entuzity, Exubera, Humulin, Humulin N, Humulin R, Insulatard, Insuman, Myxredlin, Novolin, Novolin N, Novolin R •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): High molecular weight insulin human Human insulin Insulin (human) Insulin human Insulin Human Regular Insulin recombinant human Insulin recombinant purified human Insulin regular Insulin, human Insulina regular Neutral insulin Regular Insulin, human Soluble insulin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin human is a recombinant form of human insulin used to control hyperglycemia in diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin human interact? Information: •Drug A: Buserelin •Drug B: Insulin human •Severity: MODERATE •Description: The therapeutic efficacy of Insulin human can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Human insulin is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The primary activity of insulin is the regulation of glucose metabolism. Insulin promotes glucose and amino acid uptake into muscle and adipose tissues, and other tissues except brain and liver. It also has an anabolic role in stimulating glycogen, fatty acid, and protein synthesis. Insulin inhibits gluconeogenesis in the liver. Insulin binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC) which play a critical role in metabolism and catabolism. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): When injected subcutaneously, the glucose-lowering effect of human insulin begins approximately 30 minutes post-dose. After a single subcutaneous administration of 0.1 unit/kg of human insulin to healthy subjects, peak insulin concentrations occurred between 1.5 to 2.5 hours post-dose. When administered in an inhaled form (as the product Afrezza), the time to maximum serum insulin concentration ranges from 10-20 minutes after oral inhalation of 4 to 48 units of human insulin. Serum insulin concentrations declined to baseline by approximately 60-240 minutes for these dose levels. Intrapatient variability in insulin exposure measured by AUC and Cmax is approximately 16% (95% CI 12-23%) and 21% (95% CI 16-30%), respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolism and elimination of orally inhaled human insulin are comparable to regular human insulin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral inhalation of human insulin, a mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Systemic insulin disposition (apparent terminal half-life) following oral inhalation of 4 to 48 units of human insulin was 120-206 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actraphane, Actrapid, Afrezza, Entuzity, Exubera, Humulin, Humulin N, Humulin R, Insulatard, Insuman, Myxredlin, Novolin, Novolin N, Novolin R •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): High molecular weight insulin human Human insulin Insulin (human) Insulin human Insulin Human Regular Insulin recombinant human Insulin recombinant purified human Insulin regular Insulin, human Insulina regular Neutral insulin Regular Insulin, human Soluble insulin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin human is a recombinant form of human insulin used to control hyperglycemia in diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin lispro interact?

•Drug A: Buserelin •Drug B: Insulin lispro •Severity: MODERATE •Description: The therapeutic efficacy of Insulin lispro can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin lispro is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin lispro is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin lispro is 10-15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 4-5 hours. Compared to regular human insulin, insulin lispro has a more rapid onset of action and a shorter duration of action. Insulin lispro is also shown to be equipotent to human insulin on a molar basis. Insulin lispro has been shown to be equipotent to human insulin on a molar basis. One unit of insulin lispro has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that insulin lispro has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously. The pharmacodynamics of a single 20 unit dose of insulin lispro at 200 units/mL (HUMALOG U-200) administered subcutaneously were compared to the pharmacodynamics of a single 20 unit dose of insulin lispro at 100 units/mL (HUMALOG U-100) administered subcutaneously in a euglycemic clamp study enrolling healthy subjects. In this study, the overall, maximum, and time to maximum glucose lowering effect were similar between HUMALOG U-200 and HUMALOG U-100. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) were 125 g and 126 g for HUMALOG U-200 and HUMALOG U-100, respectively. The maximum glucose infusion rate was 534 mg/min and 559 mg/min and the corresponding median time (min, max) to maximum effect were 2.8 h (0.5 h – 6.3 h) and 2.4 h (0.5 h – 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin lispro binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Reversal of the proline and lysine residues at positions B28 and B29 of native insulin eliminates hydrophobic interactions and weakens some of the hydrogen bonds that contribute to the stability of the insulin dimers that comprise insulin hexamers. Hexamers of insulin lispro are produced in the presence of zinc and m -cresol. These weakly associated hexamers quickly dissociate upon subcutaneous injection and are absorbed as monomers through vascular endothelial cells. These properties give insulin lispro its fast-acting properties. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Studies in healthy volunteers and patients with diabetes demonstrated that insulin lispro is absorbed more quickly than regular human insulin, specifically at the abdominal, deltoid, or femoral subcutaneous sites. In healthy volunteers given subcutaneous doses of insulin lispro ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. After insulin lispro was administered in the abdomen, serum drug levels were higher, and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of insulin lispro is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive. The mean observed area under the serum insulin concentration-time curve from time zero to infinity was 2360 pmol hr/L to 2390 pmol hr/L. The corresponding mean peak serum insulin concentration was 795 pmol/L to 909 pmol/L, and the median time to maximum concentration was 1.0 hour. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of HUMALOG appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively). •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of insulin lispro is identical to that of regular human insulin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): After subcutaneous administration of insulin lispro, the t 1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). For intravenous administration, insulin lispro demonstrated a mean t 1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses. •Clearance (Drug A): No clearance available •Clearance (Drug B): When administered intravenously, insulin lispro and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Rare cases of lipoatrophy or lipohypertrophy reactions have been observed. Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately. Patients with renal or hepatic impairment may be at increased risk of hypoglycemia and may require more frequent insulin lispro dose adjustment and more frequent blood glucose monitoring. Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose. Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays. Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Admelog, Humalog, Humalog Mix, Humalog kwikpen, Liprolog, Lyumjev •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin lispro is a modified form of fast-acting insulin used to control hyperglycemia in diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin lispro interact? Information: •Drug A: Buserelin •Drug B: Insulin lispro •Severity: MODERATE •Description: The therapeutic efficacy of Insulin lispro can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Insulin lispro is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin lispro is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin lispro is 10-15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 4-5 hours. Compared to regular human insulin, insulin lispro has a more rapid onset of action and a shorter duration of action. Insulin lispro is also shown to be equipotent to human insulin on a molar basis. Insulin lispro has been shown to be equipotent to human insulin on a molar basis. One unit of insulin lispro has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that insulin lispro has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously. The pharmacodynamics of a single 20 unit dose of insulin lispro at 200 units/mL (HUMALOG U-200) administered subcutaneously were compared to the pharmacodynamics of a single 20 unit dose of insulin lispro at 100 units/mL (HUMALOG U-100) administered subcutaneously in a euglycemic clamp study enrolling healthy subjects. In this study, the overall, maximum, and time to maximum glucose lowering effect were similar between HUMALOG U-200 and HUMALOG U-100. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) were 125 g and 126 g for HUMALOG U-200 and HUMALOG U-100, respectively. The maximum glucose infusion rate was 534 mg/min and 559 mg/min and the corresponding median time (min, max) to maximum effect were 2.8 h (0.5 h – 6.3 h) and 2.4 h (0.5 h – 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin lispro binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Reversal of the proline and lysine residues at positions B28 and B29 of native insulin eliminates hydrophobic interactions and weakens some of the hydrogen bonds that contribute to the stability of the insulin dimers that comprise insulin hexamers. Hexamers of insulin lispro are produced in the presence of zinc and m -cresol. These weakly associated hexamers quickly dissociate upon subcutaneous injection and are absorbed as monomers through vascular endothelial cells. These properties give insulin lispro its fast-acting properties. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Studies in healthy volunteers and patients with diabetes demonstrated that insulin lispro is absorbed more quickly than regular human insulin, specifically at the abdominal, deltoid, or femoral subcutaneous sites. In healthy volunteers given subcutaneous doses of insulin lispro ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. After insulin lispro was administered in the abdomen, serum drug levels were higher, and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of insulin lispro is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive. The mean observed area under the serum insulin concentration-time curve from time zero to infinity was 2360 pmol hr/L to 2390 pmol hr/L. The corresponding mean peak serum insulin concentration was 795 pmol/L to 909 pmol/L, and the median time to maximum concentration was 1.0 hour. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of HUMALOG appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively). •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of insulin lispro is identical to that of regular human insulin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): After subcutaneous administration of insulin lispro, the t 1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). For intravenous administration, insulin lispro demonstrated a mean t 1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses. •Clearance (Drug A): No clearance available •Clearance (Drug B): When administered intravenously, insulin lispro and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Rare cases of lipoatrophy or lipohypertrophy reactions have been observed. Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately. Patients with renal or hepatic impairment may be at increased risk of hypoglycemia and may require more frequent insulin lispro dose adjustment and more frequent blood glucose monitoring. Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose. Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays. Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Admelog, Humalog, Humalog Mix, Humalog kwikpen, Liprolog, Lyumjev •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin lispro is a modified form of fast-acting insulin used to control hyperglycemia in diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Insulin pork interact?

•Drug A: Buserelin •Drug B: Insulin pork •Severity: MODERATE •Description: The therapeutic efficacy of Insulin pork can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of type I and II diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is used in the treatment of type I and type II diabetes. The primary activity of insulin is the regulation of glucose metabolism. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly. It also promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the conversion of excess glucose into fat. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC) which play a critical role in metabolism. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Hypurin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin pork is a purified form of porcine insulin used to control hyperglycemia in diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Insulin pork interact? Information: •Drug A: Buserelin •Drug B: Insulin pork •Severity: MODERATE •Description: The therapeutic efficacy of Insulin pork can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of type I and II diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Insulin is used in the treatment of type I and type II diabetes. The primary activity of insulin is the regulation of glucose metabolism. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly. It also promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the conversion of excess glucose into fat. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Insulin binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC) which play a critical role in metabolism. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Hypurin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Insulin pork is a purified form of porcine insulin used to control hyperglycemia in diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Isoflurane interact?

•Drug A: Buserelin •Drug B: Isoflurane •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Isoflurane is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca activated potassium channel, the glutamate receptor and the glycine receptor. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Minimal •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LC50=15300 ppm/3 hrs (inhalation by rat) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Forane, Terrell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Isoflurane Isoflurano Isofluranum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Isoflurane is an inhaled general anesthetic used in surgery.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Isoflurane interact? Information: •Drug A: Buserelin •Drug B: Isoflurane •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Isoflurane is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca activated potassium channel, the glutamate receptor and the glycine receptor. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Minimal •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LC50=15300 ppm/3 hrs (inhalation by rat) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Forane, Terrell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Isoflurane Isoflurano Isofluranum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Isoflurane is an inhaled general anesthetic used in surgery. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Isradipine interact?

•Drug A: Buserelin •Drug B: Isradipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Isradipine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Isradipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of isradipine result in an overall decrease in blood pressure. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 95% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include lethargy, sinus tachycardia, and transient hypotension. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Isradipine interact? Information: •Drug A: Buserelin •Drug B: Isradipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Isradipine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Isradipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of isradipine result in an overall decrease in blood pressure. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 95% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include lethargy, sinus tachycardia, and transient hypotension. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Itraconazole interact?

•Drug A: Buserelin •Drug B: Itraconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Itraconazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy It is also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Itraconazole is an antifungal agent that inhibits cell growth and promotes cell death of fungi. It exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Itraconazole mediates its antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol, a vital component of fungal cell membranes. The azole nitrogen atoms in the chemical structure of itraconazole form a complex with the active site, or the haem iron, of the fungal enzyme to impede its function. The accumulation of lanosterol and 14-methylated sterols results in increased permeability of the fungal cell membrane, and modified membrane-bound enzyme activity, and dysregulated chitin synthesis. Other proposed mechanisms of action of itraconazole include the inhibition of fungal cytochrome c oxidative and peroxidative enzymes that also lead to the disruption of fungal cell membranes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Itraconazole is rapidly absorbed after oral administration. As oral capsules, peak plasma concentrations of itraconazole are reached within two to five hours. The observed absolute oral bioavailability of itraconazole is about 55%. Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of the drug is given. Maximal drug absorption is achieved under adequate gastric acidity. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution is more than 700 L in adults. Itraconazole is lipophilic and extensively distributed into tissues. Concentrations in the lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It also has a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as the free drug. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Itraconazole is extensively metabolized in the liver. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. While itraconazole can be metabolized to more than 30 metabolites, the main metabolite is hydroxyitraconazole. Hydroxyitraconazole has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of the parent compound. Other metabolites include keto-itraconazole and N-dealkyl-itraconazole. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxyitraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. As the re-distribution of itraconazole from keratinous tissues appears to be negligible, the elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for two to four weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as one week after the start of treatment – for at least six months after the end of a 3-month treatment period. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life of itraconazole generally ranges from 16 to 28 hours after a single dose and increases to 34 to 42 hours with repeated dosing. The metabolite of itraconazole is excreted from the plasma more rapidly than the parent compound. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In rats, the oral and intraperitoneal LD 50 values were >320 mg/kg and 100 mg/kg, respectively. There is limited clinical information regarding itraconazole overdoses. Reported toxic trough levels are over 3 mcg/mL. Itraconazole is not removed by dialysis; thus, supportive measures should be initiated in the event of an overdose. There is no known antidote to itraconazole poisoning. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sporanox, Tolsura •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Itraconazole is a triazole antifungal agent used to treat various fungal infections, such as blastomycosis and onychomycosis.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Itraconazole interact? Information: •Drug A: Buserelin •Drug B: Itraconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Itraconazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy It is also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Itraconazole is an antifungal agent that inhibits cell growth and promotes cell death of fungi. It exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Itraconazole mediates its antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol, a vital component of fungal cell membranes. The azole nitrogen atoms in the chemical structure of itraconazole form a complex with the active site, or the haem iron, of the fungal enzyme to impede its function. The accumulation of lanosterol and 14-methylated sterols results in increased permeability of the fungal cell membrane, and modified membrane-bound enzyme activity, and dysregulated chitin synthesis. Other proposed mechanisms of action of itraconazole include the inhibition of fungal cytochrome c oxidative and peroxidative enzymes that also lead to the disruption of fungal cell membranes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Itraconazole is rapidly absorbed after oral administration. As oral capsules, peak plasma concentrations of itraconazole are reached within two to five hours. The observed absolute oral bioavailability of itraconazole is about 55%. Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of the drug is given. Maximal drug absorption is achieved under adequate gastric acidity. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution is more than 700 L in adults. Itraconazole is lipophilic and extensively distributed into tissues. Concentrations in the lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It also has a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as the free drug. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Itraconazole is extensively metabolized in the liver. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. While itraconazole can be metabolized to more than 30 metabolites, the main metabolite is hydroxyitraconazole. Hydroxyitraconazole has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of the parent compound. Other metabolites include keto-itraconazole and N-dealkyl-itraconazole. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxyitraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. As the re-distribution of itraconazole from keratinous tissues appears to be negligible, the elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for two to four weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as one week after the start of treatment – for at least six months after the end of a 3-month treatment period. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life of itraconazole generally ranges from 16 to 28 hours after a single dose and increases to 34 to 42 hours with repeated dosing. The metabolite of itraconazole is excreted from the plasma more rapidly than the parent compound. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In rats, the oral and intraperitoneal LD 50 values were >320 mg/kg and 100 mg/kg, respectively. There is limited clinical information regarding itraconazole overdoses. Reported toxic trough levels are over 3 mcg/mL. Itraconazole is not removed by dialysis; thus, supportive measures should be initiated in the event of an overdose. There is no known antidote to itraconazole poisoning. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sporanox, Tolsura •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Itraconazole is a triazole antifungal agent used to treat various fungal infections, such as blastomycosis and onychomycosis. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ivabradine interact?

•Drug A: Buserelin •Drug B: Ivabradine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ivabradine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ivabradine is indicated by the FDA to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. It is also indicated for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy for pediatric patients 6 months of age or more. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The funny channels (If) open during repolarization and close during depolarization, making ivabradine's activity dependent on heart rate or the closing and opening of the channels. Therefore ivabradine exhibits use-dependence and is more pharmacologically active at higher heart rates. Ivabradine exhibits a linear dose-dependent heart-rate lowering activity (bradycardic effect) until a maximum dose of 30-40mg. At higher doses, the concentration of ivabradine tends to plateau, reducing risk of serious sinus bradycardia. It has been shown that the metabolite of ivabradine lowers heart rate as well, contributing to ivabradine's overall effect. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium). Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate. The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine therefore lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): It is recommended to take ivabradine with food to reduce variability in systemic exposure. Administration with food slows absorption by 1 hour, but increases systemic absorption by 20-30%. Ivabradine's oral bioavailability is about 40%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): ~100 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): 70% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ivabradine is extensively metabolized by oxidation in the gut and liver by cytochrome P450 3A4 enzyme. Its active metabolite, N-desmethylated derivative, is also metabolized by CYP 3A4. Ivabradine's affinity for CYP 3A4 is low, making it unlikely to affect the metabolism of other drugs; however potent inhibitors or inducers of CYP 3A4 may affect ivabradine's plasma concentration and pharmacodynamic effects and should not be co-administered. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Metabolites are equally excreted in feces and urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance is about 400ml/min; renal clearance about 70ml/min. About 4% is excreted unchanged in urine. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Ivabradine may cause fetal toxicity when administered to pregnant women. Animal studies in pregnant rats have shown embryo-fetal toxicity and cardiac teratogenic effects. Effective contraception in women is recommended while using ivabradine. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Corlanor, Lancora, Procoralan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ivabradin Ivabradina Ivabradine Ivabradinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ivabradine is a HCN channel blocker used to reduce the risk of hospitalization for worsening heart failure in adult patients and for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy in pediatric patients.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Ivabradine interact? Information: •Drug A: Buserelin •Drug B: Ivabradine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ivabradine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ivabradine is indicated by the FDA to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. It is also indicated for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy for pediatric patients 6 months of age or more. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The funny channels (If) open during repolarization and close during depolarization, making ivabradine's activity dependent on heart rate or the closing and opening of the channels. Therefore ivabradine exhibits use-dependence and is more pharmacologically active at higher heart rates. Ivabradine exhibits a linear dose-dependent heart-rate lowering activity (bradycardic effect) until a maximum dose of 30-40mg. At higher doses, the concentration of ivabradine tends to plateau, reducing risk of serious sinus bradycardia. It has been shown that the metabolite of ivabradine lowers heart rate as well, contributing to ivabradine's overall effect. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium). Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate. The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine therefore lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): It is recommended to take ivabradine with food to reduce variability in systemic exposure. Administration with food slows absorption by 1 hour, but increases systemic absorption by 20-30%. Ivabradine's oral bioavailability is about 40%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): ~100 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): 70% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ivabradine is extensively metabolized by oxidation in the gut and liver by cytochrome P450 3A4 enzyme. Its active metabolite, N-desmethylated derivative, is also metabolized by CYP 3A4. Ivabradine's affinity for CYP 3A4 is low, making it unlikely to affect the metabolism of other drugs; however potent inhibitors or inducers of CYP 3A4 may affect ivabradine's plasma concentration and pharmacodynamic effects and should not be co-administered. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Metabolites are equally excreted in feces and urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance is about 400ml/min; renal clearance about 70ml/min. About 4% is excreted unchanged in urine. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Ivabradine may cause fetal toxicity when administered to pregnant women. Animal studies in pregnant rats have shown embryo-fetal toxicity and cardiac teratogenic effects. Effective contraception in women is recommended while using ivabradine. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Corlanor, Lancora, Procoralan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ivabradin Ivabradina Ivabradine Ivabradinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ivabradine is a HCN channel blocker used to reduce the risk of hospitalization for worsening heart failure in adult patients and for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy in pediatric patients. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Ivosidenib interact?

•Drug A: Buserelin •Drug B: Ivosidenib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ivosidenib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe. It is indicated for the treatment of patients with a susceptible IDH1 mutation with: Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy. this indication is reserved for adults 75 years or older in the US. Relapsed or refractory AML in adults in the US. Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated. Relapsed or Refractory Myelodysplastic Syndromes in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, ivosidenib is rapidly absorbed. The C max following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state C max is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The T max ranges from two to three hours. A high-fat meal increases ivosidenib exposure. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro, ivosidenib is 92-96% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is limited information regarding the LD 50 or overdose of ivosidenib. Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tibsovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ivosidenib interact? Information: •Drug A: Buserelin •Drug B: Ivosidenib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ivosidenib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe. It is indicated for the treatment of patients with a susceptible IDH1 mutation with: Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy. this indication is reserved for adults 75 years or older in the US. Relapsed or refractory AML in adults in the US. Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated. Relapsed or Refractory Myelodysplastic Syndromes in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, ivosidenib is rapidly absorbed. The C max following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state C max is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The T max ranges from two to three hours. A high-fat meal increases ivosidenib exposure. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro, ivosidenib is 92-96% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is limited information regarding the LD 50 or overdose of ivosidenib. Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tibsovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ketoconazole interact?

•Drug A: Buserelin •Drug B: Ketoconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ketoconazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ketoconazole is used in the treatment or prevention of fungal infections including blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. In Europe, it is also used in the treatment of endogenous Cushing's syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ketoconazole, similarly to other azole antifungals, is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability due to reduced amounts of ergosterol present in the fungal cell membrane. This metabolic inhibition also results in accumulation of 14α-methyl-3,6-diol, a toxic metabolite. The increase in membrane fluidity is also thought to produce impairment of membrane-bound enzyme systems as components become less closely packed. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Ketoconazole requires an acidic environment to become soluble in water. At pH values above 3 it becomes increasingly insoluble with about 10% entering solution in 1 h. At pH less than 3 dissolution is 85% complete in 5 min and entirely complete within 30 min. A single 200 mg oral dose produces a Cmax of 2.5-3 mcg/mL with a Tmax of 1-4 h. Administering ketoconazole with food consistently increases Cmax and delays Tmax but literature is contradictory regarding the effect on AUC, which may experience a small decrease. A bioavailablity of 76% has been reported for ketoconazole. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Ketoconazole has an estimated volume of distribution of 25.41 L or 0.36 L/kg. It distributes widely among the tissues, reaching effective concentrations in the skin, tendons, tears, and saliva. Distribution to vaginal tissue produces concentrations 2.4 times lower than plasma. Penetration into the CNS, bone, and seminal fluid are minimal. Ketoconazole has been found to enter the breast milk and cross the placenta in animal studies. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ketoconazole is approximately 84% bound to plasma albumin with another 15% associated with blood cells for a total of 99% binding within the plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The major metabolite of ketoconazole appears to be M2, an end product resulting from oxidation of the imidazole moiety. CYP3A4 is known to be the primary contributor to this reaction with some contribution from CYP2D6. Other metabolites resulting from CYP3A4 mediated oxidation of the imidazole moiety include M3, M4, and M5. Ketoconazole may also undergo N-deacetylation to M14,, alkyl oxidation to M7, N-oxidation to M13, or aromatic hydroxylation to M8, or hydroxylation to M9. M9 may further undergo oxidation of the hydroxyl to form M12, N-dealkylation to form M10 with a subsequent N-dealkylation to M15, or may form an iminium ion. No metabolites are known to be active however oxidation metabolites of M14 have been implicated in cytotoxicity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Only 2-4% of the ketoconazole dose is eliminated unchanged in the urine. Over 95% is eliminated through hepatic metabolism. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Ketoconazole experiences biphasic elimination with the first phase having a half-life of 2 hours and a terminal half life of 8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ketoconazole has an estimated clearance of 8.66 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include acute liver injury, which may include both hepatocellular and cholestatic injury, accompanied by anorexia, fatigue, nausea, and jaundice. In case of overdose, gastric lavage with activated charcoal may be used if within one hour of ketoconazole ingestion otherwise provide supportive care. If the patient shows signs of adrenal insufficiency, administer 100 mg hydrocortisone once together with saline and glucose infusion and monitor the patient closely. Blood pressure and fluid and electrolyte balance should be monitored over the next few days. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Extina, Ketodan, Ketoderm, Nizoral, Xolegel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ketoconazole is a broad spectrum antifungal used to treat seborrheic dermatitis and fungal skin infections.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ketoconazole interact? Information: •Drug A: Buserelin •Drug B: Ketoconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ketoconazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ketoconazole is used in the treatment or prevention of fungal infections including blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. In Europe, it is also used in the treatment of endogenous Cushing's syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ketoconazole, similarly to other azole antifungals, is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability due to reduced amounts of ergosterol present in the fungal cell membrane. This metabolic inhibition also results in accumulation of 14α-methyl-3,6-diol, a toxic metabolite. The increase in membrane fluidity is also thought to produce impairment of membrane-bound enzyme systems as components become less closely packed. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Ketoconazole requires an acidic environment to become soluble in water. At pH values above 3 it becomes increasingly insoluble with about 10% entering solution in 1 h. At pH less than 3 dissolution is 85% complete in 5 min and entirely complete within 30 min. A single 200 mg oral dose produces a Cmax of 2.5-3 mcg/mL with a Tmax of 1-4 h. Administering ketoconazole with food consistently increases Cmax and delays Tmax but literature is contradictory regarding the effect on AUC, which may experience a small decrease. A bioavailablity of 76% has been reported for ketoconazole. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Ketoconazole has an estimated volume of distribution of 25.41 L or 0.36 L/kg. It distributes widely among the tissues, reaching effective concentrations in the skin, tendons, tears, and saliva. Distribution to vaginal tissue produces concentrations 2.4 times lower than plasma. Penetration into the CNS, bone, and seminal fluid are minimal. Ketoconazole has been found to enter the breast milk and cross the placenta in animal studies. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ketoconazole is approximately 84% bound to plasma albumin with another 15% associated with blood cells for a total of 99% binding within the plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The major metabolite of ketoconazole appears to be M2, an end product resulting from oxidation of the imidazole moiety. CYP3A4 is known to be the primary contributor to this reaction with some contribution from CYP2D6. Other metabolites resulting from CYP3A4 mediated oxidation of the imidazole moiety include M3, M4, and M5. Ketoconazole may also undergo N-deacetylation to M14,, alkyl oxidation to M7, N-oxidation to M13, or aromatic hydroxylation to M8, or hydroxylation to M9. M9 may further undergo oxidation of the hydroxyl to form M12, N-dealkylation to form M10 with a subsequent N-dealkylation to M15, or may form an iminium ion. No metabolites are known to be active however oxidation metabolites of M14 have been implicated in cytotoxicity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Only 2-4% of the ketoconazole dose is eliminated unchanged in the urine. Over 95% is eliminated through hepatic metabolism. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Ketoconazole experiences biphasic elimination with the first phase having a half-life of 2 hours and a terminal half life of 8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ketoconazole has an estimated clearance of 8.66 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include acute liver injury, which may include both hepatocellular and cholestatic injury, accompanied by anorexia, fatigue, nausea, and jaundice. In case of overdose, gastric lavage with activated charcoal may be used if within one hour of ketoconazole ingestion otherwise provide supportive care. If the patient shows signs of adrenal insufficiency, administer 100 mg hydrocortisone once together with saline and glucose infusion and monitor the patient closely. Blood pressure and fluid and electrolyte balance should be monitored over the next few days. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Extina, Ketodan, Ketoderm, Nizoral, Xolegel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ketoconazole is a broad spectrum antifungal used to treat seborrheic dermatitis and fungal skin infections. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Lacidipine interact?

•Drug A: Buserelin •Drug B: Lacidipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lacidipine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers. Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There have been no recorded cases of lacidipine tablets overdosage. Some of the symptoms of overdose include prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could theoretically occur. As there is no known antidote for lacidipine, the use of standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures is recommended. Oral LD50 in mouse, rabbit and rat are 300mg/kg, 3200mg/kg and 980mg/kg, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lacidipine is a lipophilic dihydropyridine calcium channel blocker with a slow onset of action used to treat hypertension.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Lacidipine interact? Information: •Drug A: Buserelin •Drug B: Lacidipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lacidipine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers. Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There have been no recorded cases of lacidipine tablets overdosage. Some of the symptoms of overdose include prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could theoretically occur. As there is no known antidote for lacidipine, the use of standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures is recommended. Oral LD50 in mouse, rabbit and rat are 300mg/kg, 3200mg/kg and 980mg/kg, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lacidipine is a lipophilic dihydropyridine calcium channel blocker with a slow onset of action used to treat hypertension. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Lamotrigine interact?

•Drug A: Buserelin •Drug B: Lamotrigine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Lamotrigine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to Lennox-Gastaut syndrome. It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy. Limitations of use It is important to note that lamotirigine should not be used in the treatment of acute mood episodes, as efficacy has not been established in this context. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Lamotrigine likely prevents seizures and prevents mood symptoms via stabilizing presynaptic neuronal membranes and preventing the release of excitatory neurotransmitters such as glutamate, which contribute to seizure activity. A note on cardiovascular effects The metabolite of lamotrigine, 2-N-methyl metabolite (formed by glucuronidation), is reported to cause dose-dependent prolongations of the PR interval, widening of the QRS complex, and at higher doses, complete AV block. Although this harmful metabolite is only found in trace amounts in humans, plasma concentrations may increase in conditions that cause decreased drug glucuronidation, such as liver disease. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanism of action of lamotrigine is not fully elucidated, as it may exert cellular activities that contribute to its efficacy in a range of conditions. Although chemically unrelated, lamotrigine actions resemble those of phenytoin and carbamazepine, inhibiting voltage-sensitive sodium channels, stabilizing neuronal membranes, thereby modulating the release of presynaptic excitatory neurotransmitters. Lamotrigine likely acts by inhibiting sodium currents by selective binding to the inactive sodium channel, suppressing the release of the excitatory amino acid, glutamate. The mechanism of action of lamotrigine in reducing anticonvulsant activity is likely the same in managing bipolar disorder. Studies on lamotrigine have identified its binding to sodium channels in a fashion similar to local anesthetics, which could explain the demonstrated clinical benefit of lamotrigine in some neuropathic pain states. Lamotrigine displays binding properties to several different receptors. In laboratory binding assays, it demonstrates weak inhibitory effect on the serotonin 5-HT3 receptor. Lamotrigine also weakly binds to Adenosine A1/A2 receptors, α1/α2/β adrenergic receptors, dopamine D1/D2 receptors, GABA A/B receptors, histamine H1 receptors, κ-opioid receptor (KOR), mACh receptors and serotonin 5-HT2 receptors with an IC50>100 µM. Weak inhibitory effects were observed at sigma opioid receptors. An in vivo study revealed evidence that lamotrigine inhibits Cav2.3 (R-type) calcium currents, which may also contribute to its anticonvulsant effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Lamotrigine is rapidly and entirely absorbed with minimal first-pass metabolism effects, with a bioavailability estimated at 98%. Cmax is reached in the range of 1.4 to 4.8 hours post-dose, but this depends on the dose administered, concomitant medications, and epileptic status. The rate and extent of lamictal absorption is considered equivalent between the compressed tablet form taken with water to that of the chewable dispersible tablets, taken with or without water. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0.9 to 1.3 L/kg and is independent of dose administered. Lamotrigine accumulated in the kidney of the male rat, and likely behaves in a similar fashion in humans. Lamotrigine also binds to tissues containing melanin, such as the eyes and pigmented skin. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of lamotrigine is estimated at 55%. This drug is not expected to undergo clinically significant interactions with other drugs via competition for protein binding sites due its lower protein binding. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lamotrigine is mainly glucuronidated, forming 2-N-glucuronide conjugate, a pharmacologically inactive metabolite. The total radioactivity detected after a 240mg radiolabeled dose of lamotrigine during clinical trials were as follows: lamotrigine as unchanged drug(10%), a 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), as well as various other minor metabolites (4%). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Lamotrigine is excreted in both the urine and feces. Following oral administration of 240 mg radiolabelled lamotrigine, about 94% of total drug and its metabolites administered is recovered in the urine and 2% is recovered in the feces. One pharmacokinetic study recovered 43 to 87% of a lamotrigine dose in the urine mainly as glucuronidated metabolites. 2-N-glucuronide is mainly excreted in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average elimination half-life of lamotrigine ranges from approximately 14-59 hours. The value is dependent on the dose administered, concomitant drug therapy, as well as disease status. One pharmacokinetic study revealed a half-life of 22.8 to 37.4 hours in healthy volunteers. It also reported that enzyme-inducing antiepileptic drugs such as pheobarbital, phenytoin, or carbamazepine decrease the half-life of lamotrigine. On the other hand, valproic acid increases the half-life of lamotrigine (in the range of 48-59 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent plasma clearance (Cl/F) ranges from 0.18 to 1.21 mL/min/kg. The values vary depending on dosing regimen, concomitant antiepileptic medications, and disease state of the individual. In one study, healthy volunteers on lamictal monotherapy showed a clearance of about 0.44 mL/min/kg after a single dose. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 in mouse and rat is 205 mg/kg and 245 mg/kg, respectively. Fatal cases of overdose of up to 15g of lamotrigine have been reported. Overdose with lamotrigine has been manifested by ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay. Though no known antidote exists for lamotrigine, hospitalization and general supportive measures should be employed in the case of a suspected lamotrigine overdose. Gastric lavage and emesis may be warranted with simultaneous protection of the airway. It is uncertain at this time whether hemodialysis is an effective means of removing lamotrigine from the sytemic circulation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lamictal •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lamotrigina Lamotrigine Lamotriginum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lamotrigine is a phenyltriazine antiepileptic used to treat some types of epilepsy and bipolar I disorder.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Lamotrigine interact? Information: •Drug A: Buserelin •Drug B: Lamotrigine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Lamotrigine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to Lennox-Gastaut syndrome. It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy. Limitations of use It is important to note that lamotirigine should not be used in the treatment of acute mood episodes, as efficacy has not been established in this context. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Lamotrigine likely prevents seizures and prevents mood symptoms via stabilizing presynaptic neuronal membranes and preventing the release of excitatory neurotransmitters such as glutamate, which contribute to seizure activity. A note on cardiovascular effects The metabolite of lamotrigine, 2-N-methyl metabolite (formed by glucuronidation), is reported to cause dose-dependent prolongations of the PR interval, widening of the QRS complex, and at higher doses, complete AV block. Although this harmful metabolite is only found in trace amounts in humans, plasma concentrations may increase in conditions that cause decreased drug glucuronidation, such as liver disease. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanism of action of lamotrigine is not fully elucidated, as it may exert cellular activities that contribute to its efficacy in a range of conditions. Although chemically unrelated, lamotrigine actions resemble those of phenytoin and carbamazepine, inhibiting voltage-sensitive sodium channels, stabilizing neuronal membranes, thereby modulating the release of presynaptic excitatory neurotransmitters. Lamotrigine likely acts by inhibiting sodium currents by selective binding to the inactive sodium channel, suppressing the release of the excitatory amino acid, glutamate. The mechanism of action of lamotrigine in reducing anticonvulsant activity is likely the same in managing bipolar disorder. Studies on lamotrigine have identified its binding to sodium channels in a fashion similar to local anesthetics, which could explain the demonstrated clinical benefit of lamotrigine in some neuropathic pain states. Lamotrigine displays binding properties to several different receptors. In laboratory binding assays, it demonstrates weak inhibitory effect on the serotonin 5-HT3 receptor. Lamotrigine also weakly binds to Adenosine A1/A2 receptors, α1/α2/β adrenergic receptors, dopamine D1/D2 receptors, GABA A/B receptors, histamine H1 receptors, κ-opioid receptor (KOR), mACh receptors and serotonin 5-HT2 receptors with an IC50>100 µM. Weak inhibitory effects were observed at sigma opioid receptors. An in vivo study revealed evidence that lamotrigine inhibits Cav2.3 (R-type) calcium currents, which may also contribute to its anticonvulsant effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Lamotrigine is rapidly and entirely absorbed with minimal first-pass metabolism effects, with a bioavailability estimated at 98%. Cmax is reached in the range of 1.4 to 4.8 hours post-dose, but this depends on the dose administered, concomitant medications, and epileptic status. The rate and extent of lamictal absorption is considered equivalent between the compressed tablet form taken with water to that of the chewable dispersible tablets, taken with or without water. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0.9 to 1.3 L/kg and is independent of dose administered. Lamotrigine accumulated in the kidney of the male rat, and likely behaves in a similar fashion in humans. Lamotrigine also binds to tissues containing melanin, such as the eyes and pigmented skin. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of lamotrigine is estimated at 55%. This drug is not expected to undergo clinically significant interactions with other drugs via competition for protein binding sites due its lower protein binding. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lamotrigine is mainly glucuronidated, forming 2-N-glucuronide conjugate, a pharmacologically inactive metabolite. The total radioactivity detected after a 240mg radiolabeled dose of lamotrigine during clinical trials were as follows: lamotrigine as unchanged drug(10%), a 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), as well as various other minor metabolites (4%). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Lamotrigine is excreted in both the urine and feces. Following oral administration of 240 mg radiolabelled lamotrigine, about 94% of total drug and its metabolites administered is recovered in the urine and 2% is recovered in the feces. One pharmacokinetic study recovered 43 to 87% of a lamotrigine dose in the urine mainly as glucuronidated metabolites. 2-N-glucuronide is mainly excreted in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average elimination half-life of lamotrigine ranges from approximately 14-59 hours. The value is dependent on the dose administered, concomitant drug therapy, as well as disease status. One pharmacokinetic study revealed a half-life of 22.8 to 37.4 hours in healthy volunteers. It also reported that enzyme-inducing antiepileptic drugs such as pheobarbital, phenytoin, or carbamazepine decrease the half-life of lamotrigine. On the other hand, valproic acid increases the half-life of lamotrigine (in the range of 48-59 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent plasma clearance (Cl/F) ranges from 0.18 to 1.21 mL/min/kg. The values vary depending on dosing regimen, concomitant antiepileptic medications, and disease state of the individual. In one study, healthy volunteers on lamictal monotherapy showed a clearance of about 0.44 mL/min/kg after a single dose. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 in mouse and rat is 205 mg/kg and 245 mg/kg, respectively. Fatal cases of overdose of up to 15g of lamotrigine have been reported. Overdose with lamotrigine has been manifested by ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay. Though no known antidote exists for lamotrigine, hospitalization and general supportive measures should be employed in the case of a suspected lamotrigine overdose. Gastric lavage and emesis may be warranted with simultaneous protection of the airway. It is uncertain at this time whether hemodialysis is an effective means of removing lamotrigine from the sytemic circulation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lamictal •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lamotrigina Lamotrigine Lamotriginum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lamotrigine is a phenyltriazine antiepileptic used to treat some types of epilepsy and bipolar I disorder. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Lapatinib interact?

•Drug A: Buserelin •Drug B: Lapatinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Lapatinib is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption following oral administration of lapatinib is incomplete and variable. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Highly bound (>99%) to albumin and alpha-1 acid glycoprotein •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tykerb, Tyverb •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lapatinib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lapatinib is an antineoplastic agent and tyrosine kinase inhibitor used for the treatment of advanced or metastatic HER-positive breast cancer in patients who received prior chemotherapeutic treatments.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Lapatinib interact? Information: •Drug A: Buserelin •Drug B: Lapatinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Lapatinib is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption following oral administration of lapatinib is incomplete and variable. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Highly bound (>99%) to albumin and alpha-1 acid glycoprotein •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tykerb, Tyverb •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lapatinib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lapatinib is an antineoplastic agent and tyrosine kinase inhibitor used for the treatment of advanced or metastatic HER-positive breast cancer in patients who received prior chemotherapeutic treatments. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Lefamulin interact?

•Drug A: Buserelin •Drug B: Lefamulin •Severity: MAJOR •Description: Lefamulin may increase the QTc-prolonging activities of Buserelin. •Extended Description: Due to additive QT interval prolonging effects, lefamulin tablets may increase the risk of other QT-prolonging agents. Although the FDA label for lefamulin states that the risk of coadministration with other QT-prolonging agents is not confirmed, awareness of this possible drug interaction is important. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. A note on QT prolongation and Clostridium difficile According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation. At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL. The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state. To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L. During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia. After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma. Animal studies demonstrate that lefamulin crosses the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults. A systematic review identifies the plasma protein binding at 80-87%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 is the main enzyme responsible for the metabolism of lefamulin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys. In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia. One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In the case of overdose with lefamulin, the patient should be monitored closely and provided with supportive treatment, according to symptoms and signs. This drug and its active metabolite are not removable by dialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xenleta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lefamulin is a pleuromutilin antibacterial used to treat community-acquired bacterial pneumonia (CABP).

Due to additive QT interval prolonging effects, lefamulin tablets may increase the risk of other QT-prolonging agents. Although the FDA label for lefamulin states that the risk of coadministration with other QT-prolonging agents is not confirmed, awareness of this possible drug interaction is important. The severity of the interaction is major.

Question: Does Buserelin and Lefamulin interact? Information: •Drug A: Buserelin •Drug B: Lefamulin •Severity: MAJOR •Description: Lefamulin may increase the QTc-prolonging activities of Buserelin. •Extended Description: Due to additive QT interval prolonging effects, lefamulin tablets may increase the risk of other QT-prolonging agents. Although the FDA label for lefamulin states that the risk of coadministration with other QT-prolonging agents is not confirmed, awareness of this possible drug interaction is important. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. A note on QT prolongation and Clostridium difficile According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation. At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL. The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state. To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L. During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia. After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma. Animal studies demonstrate that lefamulin crosses the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults. A systematic review identifies the plasma protein binding at 80-87%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 is the main enzyme responsible for the metabolism of lefamulin. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys. In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia. One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In the case of overdose with lefamulin, the patient should be monitored closely and provided with supportive treatment, according to symptoms and signs. This drug and its active metabolite are not removable by dialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xenleta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lefamulin is a pleuromutilin antibacterial used to treat community-acquired bacterial pneumonia (CABP). Output: Due to additive QT interval prolonging effects, lefamulin tablets may increase the risk of other QT-prolonging agents. Although the FDA label for lefamulin states that the risk of coadministration with other QT-prolonging agents is not confirmed, awareness of this possible drug interaction is important. The severity of the interaction is major.

Does Buserelin and Lenvatinib interact?

•Drug A: Buserelin •Drug B: Lenvatinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lenvatinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Lenvatinib is indicated for the treatment of the following cancerous conditions: Differentiated Thyroid Cancer (DTC) Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer Renal Cell Carcinoma (RCC) First-line treatment, in combination with pembrolizumab, in adult patients with advanced renal cell carcinoma (RCC) Treatment of advanced renal cell carcinoma, in combination with everolimus, in adult patients who have previously tried ≥1 anti-angiogenic therapy Hepatocellular Carcinoma (HCC) First-line treatment of patients with unresectable hepatocellular carcinoma Endometrial Carcinoma Treatment of advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), in combination with pembrolizumab, in patients who have experienced disease progression following prior systemic therapy and are not candidates for curative surgery or radiation •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Based on x-ray crystallography and kinetic interaction studies, lenvatinib binds to the adenosine 5'-triphosphate binding site of VEGFR2 and to a neighbouring region via a cyclopropane ring and thereby inhibits tyrosine kinase activity and associated signalling pathways. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Time to peak plasma concentration occurred from 1 to 4 hours post­dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lenvatinib is metabolized by CYP3A and aldehyde oxidase. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following administration of a radiolabeled dose, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half­life of lenvatinib is approximately 28 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common adverse events that occurred in lenvatinib recipients were hypertension (67.8 vs. 9.2 % in the placebo group), diarrhea (59.4 vs. 8.4 %), fatigue or asthenia (59.0 vs. 27.5 %), decreased appetite (50.2 vs. 11.5 %), decreased bodyweight (46.4 vs. 9.2 %), nausea (41.0 vs. 13.7 %), stomatitis (35.6 vs. 3.8 %), palmar-plantar erythrodysethesia syndrome (31.8 vs. 8.0 %) and proteinuria (31.0 vs. 1.5 %). Adverse events that occurred in clinical trials and for which there is a warning/precaution in US manufacturer’s pre- scribing information were hypertension, cardiac dysfunction (decreased left or right ventricular function, cardiac failure or pulmonary edema), arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcaemia, reversible posterior leucoencephalopathy syndrome, haemorrhagic events, and impairment of thyroid stimulating hormone (TSH) suppression. Based on the mechanism of action of lenvatinib and results from animal reproduction studies, which showed embryotoxicity, foetotoxicity and teratogenicity at lenvatinib doses below the recommended dose in humans, females of reproductive potential should be advised to use effective contraception during treatment and for at least 2 weeks following completion of therapy. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lenvima 10 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lenvatinib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lenvatinib is a receptor tyrosine kinase inhibitor used for the treatment of metastatic thyroid cancer, advanced renal cell carcinoma in combination with everolimus, and unresectable hepatocellular carcinoma.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Lenvatinib interact? Information: •Drug A: Buserelin •Drug B: Lenvatinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lenvatinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Lenvatinib is indicated for the treatment of the following cancerous conditions: Differentiated Thyroid Cancer (DTC) Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer Renal Cell Carcinoma (RCC) First-line treatment, in combination with pembrolizumab, in adult patients with advanced renal cell carcinoma (RCC) Treatment of advanced renal cell carcinoma, in combination with everolimus, in adult patients who have previously tried ≥1 anti-angiogenic therapy Hepatocellular Carcinoma (HCC) First-line treatment of patients with unresectable hepatocellular carcinoma Endometrial Carcinoma Treatment of advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), in combination with pembrolizumab, in patients who have experienced disease progression following prior systemic therapy and are not candidates for curative surgery or radiation •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Based on x-ray crystallography and kinetic interaction studies, lenvatinib binds to the adenosine 5'-triphosphate binding site of VEGFR2 and to a neighbouring region via a cyclopropane ring and thereby inhibits tyrosine kinase activity and associated signalling pathways. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Time to peak plasma concentration occurred from 1 to 4 hours post­dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Lenvatinib is metabolized by CYP3A and aldehyde oxidase. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following administration of a radiolabeled dose, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half­life of lenvatinib is approximately 28 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common adverse events that occurred in lenvatinib recipients were hypertension (67.8 vs. 9.2 % in the placebo group), diarrhea (59.4 vs. 8.4 %), fatigue or asthenia (59.0 vs. 27.5 %), decreased appetite (50.2 vs. 11.5 %), decreased bodyweight (46.4 vs. 9.2 %), nausea (41.0 vs. 13.7 %), stomatitis (35.6 vs. 3.8 %), palmar-plantar erythrodysethesia syndrome (31.8 vs. 8.0 %) and proteinuria (31.0 vs. 1.5 %). Adverse events that occurred in clinical trials and for which there is a warning/precaution in US manufacturer’s pre- scribing information were hypertension, cardiac dysfunction (decreased left or right ventricular function, cardiac failure or pulmonary edema), arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcaemia, reversible posterior leucoencephalopathy syndrome, haemorrhagic events, and impairment of thyroid stimulating hormone (TSH) suppression. Based on the mechanism of action of lenvatinib and results from animal reproduction studies, which showed embryotoxicity, foetotoxicity and teratogenicity at lenvatinib doses below the recommended dose in humans, females of reproductive potential should be advised to use effective contraception during treatment and for at least 2 weeks following completion of therapy. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lenvima 10 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lenvatinib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Lenvatinib is a receptor tyrosine kinase inhibitor used for the treatment of metastatic thyroid cancer, advanced renal cell carcinoma in combination with everolimus, and unresectable hepatocellular carcinoma. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Leuprolide interact?

•Drug A: Buserelin •Drug B: Leuprolide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Leuprolide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Leuprolide is indicated for the treatment of advanced prostate cancer and as palliative treatment of advanced prostate cancer. It is also used for the treatment of pediatric patients with central precocious puberty (CPP). In combination with oral norethisterone (also known as norethindrone), leuprolide is also indicated for the initial treatment of the symptoms of endometriosis. Finally, in combination with iron supplementation, leuprolide is indicated for the preoperative hematological improvement of anemic patients with uterine leiomyomata (uterine fibroids). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Leuprolide is a gonadotropin-releasing hormone (GnRH) analogue that functions as a GnRH receptor superagonist. After an initial spike in GnRH-mediated steroidal production, including testosterone and estradiol, prolonged use results in a significant drop in circulating steroid levels, in line with those produced through other forms of androgen-deprivation therapy (ADT). The corresponding hormonal/steroidal changes produce specific adverse effects in different patient populations. In women undergoing treatment for endometriosis or uterine leiomyomata, careful consideration regarding pregnancy status is advised. The initial increase in estradiol levels may worsen symptoms such as pain and bleeding. Long-term use of leuprolide is associated with loss of bone mineral density. Patients co-administered with norethisterone may experience sudden vision loss, proptosis, diplopia, migraine, thrombophlebitis, and pulmonary embolism and may also be at higher risk of cardiovascular disease. Patients with a history of depression may experience severe recurrence of depressive symptoms. In men undergoing palliative treatment for advanced/metastatic prostate cancer, short-term spikes in testosterone levels may cause tumour flare and associated symptoms such as bone pain, hematuria, neuropathy, bladder and/or ureteral obstruction, and spinal cord compression. In addition, patients are at increased risk of developing hyperglycemia, diabetes, and cardiovascular disease, which may manifest through myocardial infarction, stroke, cardiac death, or prolonged QT/QTc interval. In addition, Leuprolide may cause convulsions and embryo-fetal toxicity. In pediatric patients undergoing treatment for central precocious puberty (CPP), the initial steroidal spike may be associated with increased clinical signs of puberty within 2-4 weeks of treatment initiation. In addition, leuprolide may cause convulsions and psychiatric symptoms, including irritability, impatience, aggression, anger, and crying. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gonadotropin-releasing hormone (GnRH) is a naturally occurring decapeptide that modulates the hypothalamic-pituitary-gonadal (HPG) axis. GnRH binds to corresponding receptors (GnRHRs) on the anterior pituitary gonadotropes, which in turn release luteinizing hormone (LH) and follicle-stimulating hormone (FSH); these, in turn, affect the downstream synthesis and release of the sex hormones testosterone, dihydrotestosterone, estrone, and estradiol. Despite the variety of conditions indicated for treatment with leuprolide, the mechanism of action underlying efficacy is the same in all cases. As a GnRHR agonist, leuprolide binds to and initially activates downstream LH and FSH release; this initial spike in gonadotropin levels is responsible for some of the adverse effects associated with treatment. After 2-4 weeks of treatment, continuous stimulation of GnRHR results in feedback inhibition and significant downregulation of LH, FSH, and their corresponding downstream effects, producing a therapeutic benefit. These effects are reversible upon treatment discontinuation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Leuprolide is typically administered as a single-dose long-acting formulation employing either microsphere or biodegradable solid depot technologies. Regardless of the exact formulation and initial dose strength, the C max is typically achieved by 4-5 hours post-injection and displays large variability in the range of 4.6 - 212 ng/mL. Eventual steady-state kinetics are typically achieved by four weeks, with a narrower range of 0.1 - 2 ng/mL. No studies on the effects of food on absorption have been carried out. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Leuprolide has an apparent steady-state volume of distribution of 27 L following intravenous bolus administration to healthy males. The volume of distribution for indicated routes of subcutaneous or intramuscular injection has not been reported. •Protein binding (Drug A): 15% •Protein binding (Drug B): Leuprolide displays in vitro binding to human plasma proteins between 43% and 49%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Radiolabeling studies suggest that leuprolide is primarily metabolized to inactive penta-, tri-, and dipeptide entities, which are likely further metabolized. It is expected that various peptidases encountered throughout systemic circulation are responsible for leuprolide metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following administration of 3.75 mg leuprolide depot suspension to three patients, less than 5% of the initial dose was recovered as unchanged or pentapeptide metabolite in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Leuprolide has a terminal elimination half-life of approximately three hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Leuprolide administered as a 1 mg intravenous bolus in healthy males has a mean systemic clearance between 7.6 and 8.3 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Leuprolide is considered extremely safe, with low dose-related toxicity and comparatively mild adverse effects. Prostate cancer patients treated with leuprolide at doses as high as 20 mg/day for two years showed no additional adverse effects compared to those receiving 1 mg/day. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Camcevi, Eligard, Fensolvi, Lupaneta Pack 1-month, Lupron, Lupron Depot-ped, Viadur, Zeulide Depot •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Leuprolide is a peptide-based GnRH receptor superagonist used for the palliative treatment of prostate cancer, uterine leiomyomata, endometriosis, and central precocious puberty.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Leuprolide interact? Information: •Drug A: Buserelin •Drug B: Leuprolide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Leuprolide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Leuprolide is indicated for the treatment of advanced prostate cancer and as palliative treatment of advanced prostate cancer. It is also used for the treatment of pediatric patients with central precocious puberty (CPP). In combination with oral norethisterone (also known as norethindrone), leuprolide is also indicated for the initial treatment of the symptoms of endometriosis. Finally, in combination with iron supplementation, leuprolide is indicated for the preoperative hematological improvement of anemic patients with uterine leiomyomata (uterine fibroids). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Leuprolide is a gonadotropin-releasing hormone (GnRH) analogue that functions as a GnRH receptor superagonist. After an initial spike in GnRH-mediated steroidal production, including testosterone and estradiol, prolonged use results in a significant drop in circulating steroid levels, in line with those produced through other forms of androgen-deprivation therapy (ADT). The corresponding hormonal/steroidal changes produce specific adverse effects in different patient populations. In women undergoing treatment for endometriosis or uterine leiomyomata, careful consideration regarding pregnancy status is advised. The initial increase in estradiol levels may worsen symptoms such as pain and bleeding. Long-term use of leuprolide is associated with loss of bone mineral density. Patients co-administered with norethisterone may experience sudden vision loss, proptosis, diplopia, migraine, thrombophlebitis, and pulmonary embolism and may also be at higher risk of cardiovascular disease. Patients with a history of depression may experience severe recurrence of depressive symptoms. In men undergoing palliative treatment for advanced/metastatic prostate cancer, short-term spikes in testosterone levels may cause tumour flare and associated symptoms such as bone pain, hematuria, neuropathy, bladder and/or ureteral obstruction, and spinal cord compression. In addition, patients are at increased risk of developing hyperglycemia, diabetes, and cardiovascular disease, which may manifest through myocardial infarction, stroke, cardiac death, or prolonged QT/QTc interval. In addition, Leuprolide may cause convulsions and embryo-fetal toxicity. In pediatric patients undergoing treatment for central precocious puberty (CPP), the initial steroidal spike may be associated with increased clinical signs of puberty within 2-4 weeks of treatment initiation. In addition, leuprolide may cause convulsions and psychiatric symptoms, including irritability, impatience, aggression, anger, and crying. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Gonadotropin-releasing hormone (GnRH) is a naturally occurring decapeptide that modulates the hypothalamic-pituitary-gonadal (HPG) axis. GnRH binds to corresponding receptors (GnRHRs) on the anterior pituitary gonadotropes, which in turn release luteinizing hormone (LH) and follicle-stimulating hormone (FSH); these, in turn, affect the downstream synthesis and release of the sex hormones testosterone, dihydrotestosterone, estrone, and estradiol. Despite the variety of conditions indicated for treatment with leuprolide, the mechanism of action underlying efficacy is the same in all cases. As a GnRHR agonist, leuprolide binds to and initially activates downstream LH and FSH release; this initial spike in gonadotropin levels is responsible for some of the adverse effects associated with treatment. After 2-4 weeks of treatment, continuous stimulation of GnRHR results in feedback inhibition and significant downregulation of LH, FSH, and their corresponding downstream effects, producing a therapeutic benefit. These effects are reversible upon treatment discontinuation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Leuprolide is typically administered as a single-dose long-acting formulation employing either microsphere or biodegradable solid depot technologies. Regardless of the exact formulation and initial dose strength, the C max is typically achieved by 4-5 hours post-injection and displays large variability in the range of 4.6 - 212 ng/mL. Eventual steady-state kinetics are typically achieved by four weeks, with a narrower range of 0.1 - 2 ng/mL. No studies on the effects of food on absorption have been carried out. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Leuprolide has an apparent steady-state volume of distribution of 27 L following intravenous bolus administration to healthy males. The volume of distribution for indicated routes of subcutaneous or intramuscular injection has not been reported. •Protein binding (Drug A): 15% •Protein binding (Drug B): Leuprolide displays in vitro binding to human plasma proteins between 43% and 49%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Radiolabeling studies suggest that leuprolide is primarily metabolized to inactive penta-, tri-, and dipeptide entities, which are likely further metabolized. It is expected that various peptidases encountered throughout systemic circulation are responsible for leuprolide metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following administration of 3.75 mg leuprolide depot suspension to three patients, less than 5% of the initial dose was recovered as unchanged or pentapeptide metabolite in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Leuprolide has a terminal elimination half-life of approximately three hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Leuprolide administered as a 1 mg intravenous bolus in healthy males has a mean systemic clearance between 7.6 and 8.3 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Leuprolide is considered extremely safe, with low dose-related toxicity and comparatively mild adverse effects. Prostate cancer patients treated with leuprolide at doses as high as 20 mg/day for two years showed no additional adverse effects compared to those receiving 1 mg/day. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Camcevi, Eligard, Fensolvi, Lupaneta Pack 1-month, Lupron, Lupron Depot-ped, Viadur, Zeulide Depot •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Leuprolide is a peptide-based GnRH receptor superagonist used for the palliative treatment of prostate cancer, uterine leiomyomata, endometriosis, and central precocious puberty. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Levobupivacaine interact?

•Drug A: Buserelin •Drug B: Levobupivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Levobupivacaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Local anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean C max levels of up to 1.2 µg/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers] •Protein binding (Drug A): 15% •Protein binding (Drug B): >97% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 3.3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-bupivacaine Levobupivacaína Levobupivacaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levobupivacaine is a drug used for nerve block and anesthesia.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Levobupivacaine interact? Information: •Drug A: Buserelin •Drug B: Levobupivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Levobupivacaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Local anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean C max levels of up to 1.2 µg/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers] •Protein binding (Drug A): 15% •Protein binding (Drug B): >97% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 3.3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-bupivacaine Levobupivacaína Levobupivacaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levobupivacaine is a drug used for nerve block and anesthesia. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Levocabastine interact?

•Drug A: Buserelin •Drug B: Levocabastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Levocabastine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As an ophthalmic for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. Also used as a nasal spray for allergic rhinitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levocabastine is a selective histamine H1-receptor antagonist exerting inhibitory effects on the release of chemical mediators from mast cells and on the chemotaxis of polymorphonuclear leukocytes and eosinophils. Both histamine and antigens induced conjunctivitis can be inhibited by levocabastine. Levocabastine can also reduce symptoms of allergic rhinitis by preventing an increase in vascular permeability of nasal mucosa. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levocabastine is a potent, selective histamine H1-receptor antagonist. It works by competing with histamine for H1-receptor sites on effector cells. It thereby prevents, but does not reverse, responses mediated by histamine alone. Levocabastine does not block histamine release but, rather, prevents histamine binding and activity. Levocabastine also binds neurotensin 2 receptors and serves as a neurotensin agonist. This can induce some degree of analgesia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After instillation in the eye, levocabastine is systemically absorbed, albeit at low levels. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Mostly unchanged. 10 to 20% is metabolized to the acylglucuronide of levocabastine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 36 hours (after oral administration) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Adverse effects include visual disturbances, dry mouth, cough, nausea, eyelid edema and lacrimation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Livostin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levocabastine is a selective histamine H1 receptor antagonist indicated for the management of seasonal allergic conjunctivitis symptoms.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Levocabastine interact? Information: •Drug A: Buserelin •Drug B: Levocabastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Levocabastine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As an ophthalmic for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. Also used as a nasal spray for allergic rhinitis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levocabastine is a selective histamine H1-receptor antagonist exerting inhibitory effects on the release of chemical mediators from mast cells and on the chemotaxis of polymorphonuclear leukocytes and eosinophils. Both histamine and antigens induced conjunctivitis can be inhibited by levocabastine. Levocabastine can also reduce symptoms of allergic rhinitis by preventing an increase in vascular permeability of nasal mucosa. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levocabastine is a potent, selective histamine H1-receptor antagonist. It works by competing with histamine for H1-receptor sites on effector cells. It thereby prevents, but does not reverse, responses mediated by histamine alone. Levocabastine does not block histamine release but, rather, prevents histamine binding and activity. Levocabastine also binds neurotensin 2 receptors and serves as a neurotensin agonist. This can induce some degree of analgesia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After instillation in the eye, levocabastine is systemically absorbed, albeit at low levels. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Mostly unchanged. 10 to 20% is metabolized to the acylglucuronide of levocabastine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 36 hours (after oral administration) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Adverse effects include visual disturbances, dry mouth, cough, nausea, eyelid edema and lacrimation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Livostin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levocabastine is a selective histamine H1 receptor antagonist indicated for the management of seasonal allergic conjunctivitis symptoms. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Levocetirizine interact?

•Drug A: Buserelin •Drug B: Levocetirizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Levocetirizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Levocetirizine is indicated to treat symptoms of perennial allergic rhinitis and uncomplicated skin manifestations of chronic idiopathic urticaria. It is also used over the counter for a variety of mild allergy symptoms. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levocetirizine is a second generation histamine H 1 antagonist used to treat various allergic symptoms. It has a long duration of action as it is generally taken once daily, and a wide therapeutic window as animal studies show the maximal nonlethal dose is over 100x a normal dose. Patients are cautioned to avoid tasks that require complete alertness, avoid alertness, and use caution in patients with factors predisposing urinary retention. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levocetirizine selectively inhibits histamine H 1 receptors. This action prevents histamine from activating this receptor and causing effects like smooth muscle contraction, increased permeability of vascular endothelium, histidine uptake in basophils, stimulation of cough receptors, and stimulation of flare responses in the nervous system. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following a 5mg oral dose of levocetirizine, a C max of 0.27±0.04µg/mL with a T max of 0.75±0.50h. The AUC of levocetirizine is 2.31±0.50µg*h/mL. Taking levocetirizine with food does not affect the AUC but delays T max by 1.25 hours and lowers C max by 36%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of levocetirizine is 0.33±0.02L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding of levocetirizine was on average 96.1% 1 hour post dose and 91.9% 6 hours post dose. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Levocetirizine is poorly metabolized with 85.8% of an oral dose being excreted as the unchanged drug. Levocetirizine can be metabolized to a dihydrodiol (M2), an N-oxide (M3), a hydroxymethoxy derivative (M4), a hydroxy derivative (M5), an O-dealkylated derivative (M6), a taurine conjugate (M8), and an N-dealkylated and aromatic hydroxylated derivative (M9). The M5 metabolite can be glucuronidated to form the M1 metabolite and the M9 metabolite can form 4-chloro-4'-hydroxybenzhydryl mercapturates (M10a and M10b). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 168 hours post dose an average of 85.4% of a radiolabeled dose was recovered with an average of 80.8% in the urine and 9.5% in the feces. In the urine, 77% of the dose was recovered as unchanged drug, 0.5% as the M8 and M9 metabolites, 0.4% as the M10a metabolite, 0.4% as the M10b metabolite, 0.3% as the M3 metabolite, 0.3% as the M4 and M5 metabolite, 0.2% as the M2 metabolite, and 0.1% as the M1 metabolite. In the feces, 9.0% of the dose was recovered as unchanged drug, 1.0% as the M4 and M5 metabolite, and 0.1% as the M1 metabolite. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average half life of levocetirizine is 7.05±1.54 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average clearance of levocetirizine is 0.57±0.18mL/min/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with drowsiness. Children may become agitated and restless before drowsiness. Patients should be treated with supportive measures. Dialysis will not assist in removing the drug from the body. The maximal nonlethal dose in mice and rats is 240mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xyzal •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Levocetirizina Levocetirizine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levocetirizine is an H1-receptor antagonist used to treat symptoms associated with chronic allergic rhinitis and uncomplicated cases of chronic idiopathic urticaria.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Levocetirizine interact? Information: •Drug A: Buserelin •Drug B: Levocetirizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Levocetirizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Levocetirizine is indicated to treat symptoms of perennial allergic rhinitis and uncomplicated skin manifestations of chronic idiopathic urticaria. It is also used over the counter for a variety of mild allergy symptoms. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levocetirizine is a second generation histamine H 1 antagonist used to treat various allergic symptoms. It has a long duration of action as it is generally taken once daily, and a wide therapeutic window as animal studies show the maximal nonlethal dose is over 100x a normal dose. Patients are cautioned to avoid tasks that require complete alertness, avoid alertness, and use caution in patients with factors predisposing urinary retention. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levocetirizine selectively inhibits histamine H 1 receptors. This action prevents histamine from activating this receptor and causing effects like smooth muscle contraction, increased permeability of vascular endothelium, histidine uptake in basophils, stimulation of cough receptors, and stimulation of flare responses in the nervous system. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following a 5mg oral dose of levocetirizine, a C max of 0.27±0.04µg/mL with a T max of 0.75±0.50h. The AUC of levocetirizine is 2.31±0.50µg*h/mL. Taking levocetirizine with food does not affect the AUC but delays T max by 1.25 hours and lowers C max by 36%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of levocetirizine is 0.33±0.02L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding of levocetirizine was on average 96.1% 1 hour post dose and 91.9% 6 hours post dose. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Levocetirizine is poorly metabolized with 85.8% of an oral dose being excreted as the unchanged drug. Levocetirizine can be metabolized to a dihydrodiol (M2), an N-oxide (M3), a hydroxymethoxy derivative (M4), a hydroxy derivative (M5), an O-dealkylated derivative (M6), a taurine conjugate (M8), and an N-dealkylated and aromatic hydroxylated derivative (M9). The M5 metabolite can be glucuronidated to form the M1 metabolite and the M9 metabolite can form 4-chloro-4'-hydroxybenzhydryl mercapturates (M10a and M10b). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 168 hours post dose an average of 85.4% of a radiolabeled dose was recovered with an average of 80.8% in the urine and 9.5% in the feces. In the urine, 77% of the dose was recovered as unchanged drug, 0.5% as the M8 and M9 metabolites, 0.4% as the M10a metabolite, 0.4% as the M10b metabolite, 0.3% as the M3 metabolite, 0.3% as the M4 and M5 metabolite, 0.2% as the M2 metabolite, and 0.1% as the M1 metabolite. In the feces, 9.0% of the dose was recovered as unchanged drug, 1.0% as the M4 and M5 metabolite, and 0.1% as the M1 metabolite. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average half life of levocetirizine is 7.05±1.54 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average clearance of levocetirizine is 0.57±0.18mL/min/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with drowsiness. Children may become agitated and restless before drowsiness. Patients should be treated with supportive measures. Dialysis will not assist in removing the drug from the body. The maximal nonlethal dose in mice and rats is 240mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xyzal •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Levocetirizina Levocetirizine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levocetirizine is an H1-receptor antagonist used to treat symptoms associated with chronic allergic rhinitis and uncomplicated cases of chronic idiopathic urticaria. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Levofloxacin interact?

•Drug A: Buserelin •Drug B: Levofloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Levofloxacin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In oral and intravenous formulations, levofloxacin is indicated in adults for the treatment of various infections caused by susceptible bacteria, including infections of the upper respiratory tract, lower respiratory tract, skin, skin structures, urinary tract, and prostate. The oral formulation is also indicated in both adults and children 6 months of age and older for the post-exposure management of inhalational anthrax caused by Bacillus anthracis and for the treatment and/or prophylaxis of plague caused by Yersinia pestis. In its ophthalmic formulation, levofloxacin is indicated for the treatment of bacterial conjunctivitis caused by susceptible organisms. An inhalational solution available in Canada is indicated for the management of cystic fibrosis patients aged 18 years or older with chronic pulmonary Pseudomonas aeruginosa infections. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levofloxacin is bactericidal and exerts its antimicrobial effects via inhibition of bacterial DNA replication. It has a relatively long duration of action in comparison with other antibiotics that allows for once or twice daily dosing. Levofloxacin is associated with QTc-interval prolongation and should be used with caution in patients with other risk factors for prolongation (e.g. hypokalemia, concomitant medications). Levofloxacin has demonstrated in vitro activity against a number of aerobic gram-positive and gram-negative bacteria and may carry some activity against certain species of anaerobic bacteria and other pathogens such as Chlamydia and Legionella. Resistance to levofloxacin may develop, and is generally due to mutations in DNA gyrase or topoisomerase IV, or via alterations to drug efflux. Cross-resistance may occur between levofloxacin and other fluoroquinolones, but is unlikely to develop between levofloxacin and other antibiotic classes (e.g. macrolides) due to significant differences in chemical structure and mechanism of action. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levofloxacin, like other fluoroquinolone antibiotics, exerts its antimicrobial activity via the inhibition of two key bacterial enzymes: DNA gyrase and topoisomerase IV. Both targets are type II topoisomerases, but have unique functions within the bacterial cell. DNA gyrase is an enzyme found only in bacteria that introduces negative supercoils into DNA during replication - this helps to relieve torsional strain caused by the introduction of positive supercoils during replication, and these negative supercoils are essential for chromosome condensation and the promotion of transcription initiation. It is comprised of four subunits (two A subunits and two B subunits) of which the A subunits appear to be the target of fluoroquinolone antibiotics. Bacterial topoisomerase IV, in addition to contributing to the relaxation of positive supercoils, is essential at the terminal stages of DNA replication and functions to “unlink” newly replicated chromosomes to allow for the completion of cell division. Inhibition of these enzymes by levofloxacin likely occurs via complexation with the topoisomerase enzymes. The end result is a blockade of DNA replication, thus inhibiting cell division and resulting in cell death. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of levofloxacin following oral administration is rapid and essentially complete, with an oral bioavailability of approximately 99%. Due to its nearly complete absorption, the intravenous and oral formulations of levofloxacin may be interchangeable. The T max is generally attained 1-2 hours following administration and the C max is proportional to the given dose - an intravenous dose of 500mg infused over 60 minutes resulted in a C max of 6.2 ± 1.0 µg/mL whereas a 750mg dose infused over 90 minutes resulted in a C max of 11.5 ± 4.0 µg/mL. Oral administration with food prolongs the T max by approximately 1 hour and slightly decreases the C max, but these changes are not likely to be clinically significant. Systemic absorption following oral inhalation is approximately 50% lower than that observed following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Levofloxacin is widely distributed in the body, with an average volume of distribution following oral administration between 1.09-1.26 L/kg (~89-112 L). Concentrations in many tissues and fluids may exceed those observed in plasma. Levofloxacin is known to penetrate well into skin tissue, fluids (e.g. blisters), lung tissue, and prostatic tissue, amongst others. •Protein binding (Drug A): 15% •Protein binding (Drug B): Levofloxacin is 24-38% protein-bound in plasma, primarily to albumin. The extent of protein-binding is independent of its plasma concentration. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Only 2 metabolites, desmethyl-levofloxacin and levofloxacin-N-oxide, have been identified in humans, neither of which appears to carry any relevant pharmacological activity. Following oral administration, less than 5% of the administered dose was recovered in the urine as these metabolites, indicating very little metabolism of levofloxacin in humans. The specific enzymes responsible for the demethylation and oxidation of levofloxacin have yet to be ascertained. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The majority of administered levofloxacin is excreted unchanged in the urine. Following the administration of a single oral dose of levofloxacin, approximately 87% was eliminated unchanged in the urine within 48 hours and less than 4% was eliminated in the feces within 72 hours. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average terminal elimination half-life of levofloxacin is 6-8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average apparent total body clearance of levofloxacin ranges from 8.64-13.56 L/h, and its renal clearance ranges from 5.76-8.52 L/h. The relative similarity of these ranges indicates a small degree of non-renal clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The LD 50 following oral administration in mice and rats is 1803 mg/kg and 1478 mg/kg, respectively. Levofloxacin exhibits low potential for acute toxicity - following a single high dose of levofloxacin in several different test animals (e.g. mice, rats, monkeys) observed symptoms included ataxia, ptosis, decreased motor activity, dyspnea, tremors, and convulsions. Treatment of acute overdosage should involve stomach emptying (e.g. with activated charcoal) and general supportive measures. Consider monitoring of the patient's ECG to ensure QTc values remain within range. Levofloxacin is not efficiently removed by dialysis (peritoneal or hemodialysis) and is therefore of little benefit in cases of overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Levaquin, Quinsair •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Ofloxacin L-Ofloxacin Levofloxacin Levofloxacine Levofloxacino Levofloxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levofloxacin is a fluoroquinolone antibiotic used to treat infections caused by susceptible bacteria of the upper respiratory tract, skin and skin structures, urinary tract, and prostate, as well as for post-exposure treatment of inhaled anthrax and the plague.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Levofloxacin interact? Information: •Drug A: Buserelin •Drug B: Levofloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Levofloxacin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In oral and intravenous formulations, levofloxacin is indicated in adults for the treatment of various infections caused by susceptible bacteria, including infections of the upper respiratory tract, lower respiratory tract, skin, skin structures, urinary tract, and prostate. The oral formulation is also indicated in both adults and children 6 months of age and older for the post-exposure management of inhalational anthrax caused by Bacillus anthracis and for the treatment and/or prophylaxis of plague caused by Yersinia pestis. In its ophthalmic formulation, levofloxacin is indicated for the treatment of bacterial conjunctivitis caused by susceptible organisms. An inhalational solution available in Canada is indicated for the management of cystic fibrosis patients aged 18 years or older with chronic pulmonary Pseudomonas aeruginosa infections. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levofloxacin is bactericidal and exerts its antimicrobial effects via inhibition of bacterial DNA replication. It has a relatively long duration of action in comparison with other antibiotics that allows for once or twice daily dosing. Levofloxacin is associated with QTc-interval prolongation and should be used with caution in patients with other risk factors for prolongation (e.g. hypokalemia, concomitant medications). Levofloxacin has demonstrated in vitro activity against a number of aerobic gram-positive and gram-negative bacteria and may carry some activity against certain species of anaerobic bacteria and other pathogens such as Chlamydia and Legionella. Resistance to levofloxacin may develop, and is generally due to mutations in DNA gyrase or topoisomerase IV, or via alterations to drug efflux. Cross-resistance may occur between levofloxacin and other fluoroquinolones, but is unlikely to develop between levofloxacin and other antibiotic classes (e.g. macrolides) due to significant differences in chemical structure and mechanism of action. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levofloxacin, like other fluoroquinolone antibiotics, exerts its antimicrobial activity via the inhibition of two key bacterial enzymes: DNA gyrase and topoisomerase IV. Both targets are type II topoisomerases, but have unique functions within the bacterial cell. DNA gyrase is an enzyme found only in bacteria that introduces negative supercoils into DNA during replication - this helps to relieve torsional strain caused by the introduction of positive supercoils during replication, and these negative supercoils are essential for chromosome condensation and the promotion of transcription initiation. It is comprised of four subunits (two A subunits and two B subunits) of which the A subunits appear to be the target of fluoroquinolone antibiotics. Bacterial topoisomerase IV, in addition to contributing to the relaxation of positive supercoils, is essential at the terminal stages of DNA replication and functions to “unlink” newly replicated chromosomes to allow for the completion of cell division. Inhibition of these enzymes by levofloxacin likely occurs via complexation with the topoisomerase enzymes. The end result is a blockade of DNA replication, thus inhibiting cell division and resulting in cell death. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of levofloxacin following oral administration is rapid and essentially complete, with an oral bioavailability of approximately 99%. Due to its nearly complete absorption, the intravenous and oral formulations of levofloxacin may be interchangeable. The T max is generally attained 1-2 hours following administration and the C max is proportional to the given dose - an intravenous dose of 500mg infused over 60 minutes resulted in a C max of 6.2 ± 1.0 µg/mL whereas a 750mg dose infused over 90 minutes resulted in a C max of 11.5 ± 4.0 µg/mL. Oral administration with food prolongs the T max by approximately 1 hour and slightly decreases the C max, but these changes are not likely to be clinically significant. Systemic absorption following oral inhalation is approximately 50% lower than that observed following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Levofloxacin is widely distributed in the body, with an average volume of distribution following oral administration between 1.09-1.26 L/kg (~89-112 L). Concentrations in many tissues and fluids may exceed those observed in plasma. Levofloxacin is known to penetrate well into skin tissue, fluids (e.g. blisters), lung tissue, and prostatic tissue, amongst others. •Protein binding (Drug A): 15% •Protein binding (Drug B): Levofloxacin is 24-38% protein-bound in plasma, primarily to albumin. The extent of protein-binding is independent of its plasma concentration. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Only 2 metabolites, desmethyl-levofloxacin and levofloxacin-N-oxide, have been identified in humans, neither of which appears to carry any relevant pharmacological activity. Following oral administration, less than 5% of the administered dose was recovered in the urine as these metabolites, indicating very little metabolism of levofloxacin in humans. The specific enzymes responsible for the demethylation and oxidation of levofloxacin have yet to be ascertained. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The majority of administered levofloxacin is excreted unchanged in the urine. Following the administration of a single oral dose of levofloxacin, approximately 87% was eliminated unchanged in the urine within 48 hours and less than 4% was eliminated in the feces within 72 hours. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average terminal elimination half-life of levofloxacin is 6-8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average apparent total body clearance of levofloxacin ranges from 8.64-13.56 L/h, and its renal clearance ranges from 5.76-8.52 L/h. The relative similarity of these ranges indicates a small degree of non-renal clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The LD 50 following oral administration in mice and rats is 1803 mg/kg and 1478 mg/kg, respectively. Levofloxacin exhibits low potential for acute toxicity - following a single high dose of levofloxacin in several different test animals (e.g. mice, rats, monkeys) observed symptoms included ataxia, ptosis, decreased motor activity, dyspnea, tremors, and convulsions. Treatment of acute overdosage should involve stomach emptying (e.g. with activated charcoal) and general supportive measures. Consider monitoring of the patient's ECG to ensure QTc values remain within range. Levofloxacin is not efficiently removed by dialysis (peritoneal or hemodialysis) and is therefore of little benefit in cases of overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Levaquin, Quinsair •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Ofloxacin L-Ofloxacin Levofloxacin Levofloxacine Levofloxacino Levofloxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levofloxacin is a fluoroquinolone antibiotic used to treat infections caused by susceptible bacteria of the upper respiratory tract, skin and skin structures, urinary tract, and prostate, as well as for post-exposure treatment of inhaled anthrax and the plague. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Levomenthol interact?

•Drug A: Buserelin •Drug B: Levomenthol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Levomenthol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Protein binding (Drug A): 15% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Clearance (Drug A): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Brand Names (Drug A): Suprefact •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Summary not found

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Levomenthol interact? Information: •Drug A: Buserelin •Drug B: Levomenthol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Levomenthol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Protein binding (Drug A): 15% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Clearance (Drug A): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Brand Names (Drug A): Suprefact •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Summary not found Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Levosimendan interact?

•Drug A: Buserelin •Drug B: Levosimendan •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Levosimendan. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levosimendan is a new Ca -sensitizing inotropic agent. Ca sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 98% bound to plasma protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Eliminination half-life is approximately 1 hour. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levosimendan is a calcium sensitizer indicated to treat acutely decompensated severe chronic heart failure.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Levosimendan interact? Information: •Drug A: Buserelin •Drug B: Levosimendan •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Levosimendan. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Levosimendan is a new Ca -sensitizing inotropic agent. Ca sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 98% bound to plasma protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Eliminination half-life is approximately 1 hour. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Levosimendan is a calcium sensitizer indicated to treat acutely decompensated severe chronic heart failure. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.