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Do Buserelin and Tolterodine interact with each other?

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.

What is the risk level of combining Buserelin and Tolterodine?

Minor

Can Buserelin and Toremifene be taken together?

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 metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of 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): Toremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein. 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): Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors. 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 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): 580 L Protein binding (Drug A): 15% Protein binding (Drug B): Toremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum. 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. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency 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): Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. 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): 5 days Clearance (Drug A): No clearance available Clearance (Drug B): 5 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): Fareston 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): Toremifene is a first generation nonsteroidal selective estrogen receptor modulator used to treat certain breast 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.

How severe is the interaction between Buserelin and Toremifene?

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 metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of 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): Toremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein. 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): Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors. 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 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): 580 L Protein binding (Drug A): 15% Protein binding (Drug B): Toremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum. 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. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency 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): Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. 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): 5 days Clearance (Drug A): No clearance available Clearance (Drug B): 5 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): Fareston 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): Toremifene is a first generation nonsteroidal selective estrogen receptor modulator used to treat certain breast cancers.

Moderate

Is there an interaction between Buserelin and Trazodone?

The combination of trazodone, a cardiac QT-interval prolonging agent, may potentiate drugs that also increase the QT interval. This may lead to arrhythmia, possibly resulting in death.

How severe is the interaction between Buserelin and Trazodone?

Major

Do Buserelin and Treprostinil interact with each other?

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.

How severe is the interaction between Buserelin and Treprostinil?

Minor

Do Buserelin and Triclabendazole interact with each other?

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): This drug is indicated for the treatment of fascioliasis in patients aged 6 years old and above. 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): Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths. Effect on QT interval This drug may prolong the cardiac QT interval. Monitor ECG in patients with a history of QT prolongation or who are taking medications known to 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): Triclabendazole is an anthelmintic agent against Fasciola species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites ( sulfoxide and sulfone ) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. A note on resistance In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. 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 a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. Effect of Food Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed subjects. 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 (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg. Protein binding (Drug A): 15% Protein binding (Drug B): Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% 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): Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, 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): No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found 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 plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 hours, respectively. 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): Oral LD50 (rat): >8 gm/kg; Oral LD50 (mouse): >8 gm/kg A note on the use in pregnancy There are no available data on triclabendazole use in pregnant women to calculate a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not demonstrated an increased risk of increased fetal abnormalities with exposure to triclabendazole during the organogenesis period at doses which were about 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg. Carcinogenesis/Mutagenesis No genotoxic risk was noted for triclabendazole tested in 6 genotoxicity in vitro and in vivo assays. Impairment of Fertility No drug-related effects on reproductive performance, mating ratios or indices of fertility have been observed in a 2-generation reproductive and developmental toxicity study in rats. A note on use in breastfeeding There are no human findings on the presence of triclabendazole in milk, the effects on a nursing infant, or the effects on maternal milk production. The results of animal studies indicate that triclabendazole is found in goat milk when given as a single dose to a lactating female goat. When a drug is found to be present in animal milk, the likelihood that it will be found in human milk is high. Excercise caution if this drug is administered during nursing. Brand Names (Drug A): Suprefact Brand Names (Drug B): Egaten 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): Triclabendazole is an anthelmintic drug used to treat fascioliasis.

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.

What is the risk level of combining Buserelin and Triclabendazole?

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): This drug is indicated for the treatment of fascioliasis in patients aged 6 years old and above. 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): Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths. Effect on QT interval This drug may prolong the cardiac QT interval. Monitor ECG in patients with a history of QT prolongation or who are taking medications known to 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): Triclabendazole is an anthelmintic agent against Fasciola species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites ( sulfoxide and sulfone ) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. A note on resistance In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. 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 a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. Effect of Food Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed subjects. 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 (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg. Protein binding (Drug A): 15% Protein binding (Drug B): Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% 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): Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, 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): No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found 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 plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 hours, respectively. 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): Oral LD50 (rat): >8 gm/kg; Oral LD50 (mouse): >8 gm/kg A note on the use in pregnancy There are no available data on triclabendazole use in pregnant women to calculate a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not demonstrated an increased risk of increased fetal abnormalities with exposure to triclabendazole during the organogenesis period at doses which were about 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg. Carcinogenesis/Mutagenesis No genotoxic risk was noted for triclabendazole tested in 6 genotoxicity in vitro and in vivo assays. Impairment of Fertility No drug-related effects on reproductive performance, mating ratios or indices of fertility have been observed in a 2-generation reproductive and developmental toxicity study in rats. A note on use in breastfeeding There are no human findings on the presence of triclabendazole in milk, the effects on a nursing infant, or the effects on maternal milk production. The results of animal studies indicate that triclabendazole is found in goat milk when given as a single dose to a lactating female goat. When a drug is found to be present in animal milk, the likelihood that it will be found in human milk is high. Excercise caution if this drug is administered during nursing. Brand Names (Drug A): Suprefact Brand Names (Drug B): Egaten 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): Triclabendazole is an anthelmintic drug used to treat fascioliasis.

Minor

How do Buserelin and Trimebutine interact?

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.

What is the risk level of combining Buserelin and Trimebutine?

Minor

Can Buserelin and Trimipramine be taken together?

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.

What is the severity of the interaction when Buserelin and Trimipramine are co-administered?

Minor

Do Buserelin and Triprolidine interact with each other?

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.

What is the severity of the interaction when Buserelin and Triprolidine are co-administered?

Minor

Do Buserelin and Triptorelin interact with each other?

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.

What is the severity of the interaction when Buserelin and Triptorelin are co-administered?

Minor

Is there an interaction between Buserelin and Trovafloxacin?

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.

What is the risk level of combining Buserelin and Trovafloxacin?

Moderate

Do Buserelin and Valproic acid interact with each other?

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: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. 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): Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate 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): The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective 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): The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 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): 11 L/1.73m. Protein binding (Drug A): 15% Protein binding (Drug B): Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. 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): Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. 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): Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged 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): 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours. Clearance (Drug A): No clearance available Clearance (Drug B): 0.56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. 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 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. Brand Names (Drug A): Suprefact Brand Names (Drug B): Depakene, Depakote, Epival Synonyms (Drug A): No synonyms listed Synonyms (Drug B): acide valproïque ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure 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): Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

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.

What is the risk level of combining Buserelin and Valproic acid?

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: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. 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): Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate 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): The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective 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): The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 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): 11 L/1.73m. Protein binding (Drug A): 15% Protein binding (Drug B): Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. 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): Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. 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): Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged 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): 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours. Clearance (Drug A): No clearance available Clearance (Drug B): 0.56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. 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 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. Brand Names (Drug A): Suprefact Brand Names (Drug B): Depakene, Depakote, Epival Synonyms (Drug A): No synonyms listed Synonyms (Drug B): acide valproïque ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure 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): Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

Moderate

Can Buserelin and Vandetanib be taken together?

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): Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Because Vandetanib can prolong the Q-T interval, it is contraindicated for use in patients with serious cardiac complications such as congenital long QT syndrome and uncompensated 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): Mean IC50 of approximately 2.1 μg/mL. 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): ZD-6474 is a potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases. VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU. 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): Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months. 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): Vd of about 7450 L. Protein binding (Drug A): 15% Protein binding (Drug B): Protein binding of about 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): Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3. 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 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% 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): Median half life of 19 days. 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): Caprelsa Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Vandetanib 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): Vandetanib is an antineoplastic kinase inhibitor used to treat symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

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.

What is the severity of the interaction when Buserelin and Vandetanib are co-administered?

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): Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Because Vandetanib can prolong the Q-T interval, it is contraindicated for use in patients with serious cardiac complications such as congenital long QT syndrome and uncompensated 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): Mean IC50 of approximately 2.1 μg/mL. 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): ZD-6474 is a potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases. VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU. 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): Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months. 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): Vd of about 7450 L. Protein binding (Drug A): 15% Protein binding (Drug B): Protein binding of about 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): Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3. 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 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% 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): Median half life of 19 days. 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): Caprelsa Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Vandetanib 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): Vandetanib is an antineoplastic kinase inhibitor used to treat symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Moderate

Do Buserelin and Vardenafil interact with each other?

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.

What is the severity of the interaction when Buserelin and Vardenafil are co-administered?

Minor

Can Buserelin and Vemurafenib be taken together?

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.

What is the severity of the interaction when Buserelin and Vemurafenib are co-administered?

Moderate

Do Buserelin and Vernakalant interact with each other?

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.

What is the risk level of combining Buserelin and Vernakalant?

Minor

Do Buserelin and Vilanterol interact with each other?

Vilanterol, like other beta-agonists, has been reported to cause cardiovascular side effects, including QT prolongation, due to sympathetic activation. Therefore, the co-administration of vilanterol with other QT-prolonging agents could further increase the risk of QT prolongation.

What is the severity of the interaction when Buserelin and Vilanterol are co-administered?

Moderate

Do Buserelin and Vildagliptin interact with each other?

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.

What is the risk level of combining Buserelin and Vildagliptin?

Moderate

Do Buserelin and Voriconazole interact with each other?

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.

What is the risk level of combining Buserelin and Voriconazole?

Minor

Is there an interaction between Buserelin and Vorinostat?

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.

How severe is the interaction between Buserelin and Vorinostat?

Minor

Do Buserelin and Ziprasidone interact with each other?

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 its oral form, ziprasidone is approved for the treatment of schizophrenia, as monotherapy for acute treatment of manic or mixed episodes related to bipolar I disorder, and as adjunctive therapy to lithium or valproate for maintenance treatment of bipolar I disorder. The injectable formulation is approved only for treatment of acute agitation in 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): Ziprasidone is classified as a "second generation" or "atypical" antipsychotic and is a dopamine and 5HT2A receptor antagonist with a unique receptor binding profile. As previously mentioned, ziprasidone has a very high 5-HT2A/D2 affinity ratio, binds to multiple serotonin receptors in addition to 5-HT2A, and blocks monoamine transporters which prevents 5HT and NE reuptake. On the other hand, ziprasidone has a low affinity for muscarinic cholinergic M1, histamine H1, and alpha1-adrenergic 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 effects of ziprasidone are differentiated from other antispychotics based on its preference and affinity for certain receptors. Ziprasidone binds to serotonin-2A (5-HT2A) and dopamine D2 receptors in a similar fashion to other atypical antipsychotics; however, one key difference is that ziprasidone has a higher 5-HT2A/D2 receptor affinity ratio when compared to other antipsychotics such as olanzapine, quetiapine, risperidone, and aripiprazole. Ziprasidone offers enhanced modulation of mood, notable negative symptom relief, overall cognitive improvement and reduced motor dysfunction which is linked to it's potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in brain tissue. Ziprasidone can bind moderately to norepinephrine and serotonin reuptake sites which may contribute to its antidepressant and anxiolytic activity. Patient's taking ziprasidone will likely experience a lower incidence of orthostatic hypotension, cognitive disturbance, sedation, weight gain, and disruption in prolactin levels since ziprasidone has a lower affinity for histamine H1, muscarinic M1, and alpha1-adrenoceptors. 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 the absence of food, ziprasidone's oral bioavailability is 60%, and absorption may reach 100% if ziprasidone is taken with a meal containing at least 500 kcal. The difference in bioavailability has little to do with the fat content of the food and appears to be related to the bulk of the meal since more absorption occurs the longer ziprasidone remains in the stomach. 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 Ziprasidone is 1.5 L/kg. Protein binding (Drug A): 15% Protein binding (Drug B): Ziprasidone is extensively protein bound with over 99% of the drug bound to plasma proteins, primarily albumin and alpha1-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): Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted unchanged in the urine. The primary reductive pathway is catalyzed by aldehyde oxidase, while 2 other less prominent oxidative pathways are catalyzed by CYP3A4. Ziprasidone is unlikely to interact with other medications metabolized by CYP3A4 since only 1/3 of the antipsychotic is metabolized by the CYP3A4 system. There are 12 identified ziprasidone metabolites (abbreviations italicized): Ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid ( OX-COOH ), OX-COOH glucuronide, 3-(piperazine-1-yl)-1,2-benzisothiazole ( BITP ), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-Methyl-dihydro-ziprasidone, S-Methyl-dihydro-ziprasidone-sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one ( OX-P ), and dihydro-ziprasidone-sulfone. As suggested by the quantity of metabolites, ziprasidone is metabolized through several different pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, and oxidative N-dealkylation of ziprasidone produces OX-COOH and BITP. OX-COOH undergoes phase II metabolism to yield a glucuronidated metabolite while BITP is sequentially oxidized into BITP sulfoxide, BITP sulfone, then BITP sulfone lactam. Ziprasidone can also undergo reductive cleavage and methylation to produce S-Methyl-dihydro-ziprasidone and then further oxidation to produce S-Methyl-dihydro-ziprasidone-sulfoxide. Finally dearylation of ziprasidone produces OX-P, and the process of hydration and oxidation transforms the parent drug into dihydro-ziprasidone-sulfone. Although CYP3A4 and aldehyde oxidase are the primary enzymes involved in ziprasidone metabolism, the pathways associated with each enzyme have not been specified. 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): Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as 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 half life of ziprasidone is 6-7 hours. Clearance (Drug A): No clearance available Clearance (Drug B): The mean apparent systemic clearance is 7.5 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): The most common adverse reactions reported with ziprasidone include somnolence, respiratory tract infections, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting, headache and nausea. Brand Names (Drug A): Suprefact Brand Names (Drug B): Geodon, Zeldox 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): Ziprasidone is an atypical antipsychotic used to manage schizophrenia, bipolar mania, and agitation in patients with schizophrenia.

Ziprasidone use may lead to QTc prolongation and co-administration of ziprasidone with other QTc prolonging agents can compound this risk. 2,3 The severity of the interaction is major.

How severe is the interaction between Buserelin and Ziprasidone?

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 its oral form, ziprasidone is approved for the treatment of schizophrenia, as monotherapy for acute treatment of manic or mixed episodes related to bipolar I disorder, and as adjunctive therapy to lithium or valproate for maintenance treatment of bipolar I disorder. The injectable formulation is approved only for treatment of acute agitation in 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): Ziprasidone is classified as a "second generation" or "atypical" antipsychotic and is a dopamine and 5HT2A receptor antagonist with a unique receptor binding profile. As previously mentioned, ziprasidone has a very high 5-HT2A/D2 affinity ratio, binds to multiple serotonin receptors in addition to 5-HT2A, and blocks monoamine transporters which prevents 5HT and NE reuptake. On the other hand, ziprasidone has a low affinity for muscarinic cholinergic M1, histamine H1, and alpha1-adrenergic 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 effects of ziprasidone are differentiated from other antispychotics based on its preference and affinity for certain receptors. Ziprasidone binds to serotonin-2A (5-HT2A) and dopamine D2 receptors in a similar fashion to other atypical antipsychotics; however, one key difference is that ziprasidone has a higher 5-HT2A/D2 receptor affinity ratio when compared to other antipsychotics such as olanzapine, quetiapine, risperidone, and aripiprazole. Ziprasidone offers enhanced modulation of mood, notable negative symptom relief, overall cognitive improvement and reduced motor dysfunction which is linked to it's potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in brain tissue. Ziprasidone can bind moderately to norepinephrine and serotonin reuptake sites which may contribute to its antidepressant and anxiolytic activity. Patient's taking ziprasidone will likely experience a lower incidence of orthostatic hypotension, cognitive disturbance, sedation, weight gain, and disruption in prolactin levels since ziprasidone has a lower affinity for histamine H1, muscarinic M1, and alpha1-adrenoceptors. 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 the absence of food, ziprasidone's oral bioavailability is 60%, and absorption may reach 100% if ziprasidone is taken with a meal containing at least 500 kcal. The difference in bioavailability has little to do with the fat content of the food and appears to be related to the bulk of the meal since more absorption occurs the longer ziprasidone remains in the stomach. 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 Ziprasidone is 1.5 L/kg. Protein binding (Drug A): 15% Protein binding (Drug B): Ziprasidone is extensively protein bound with over 99% of the drug bound to plasma proteins, primarily albumin and alpha1-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): Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted unchanged in the urine. The primary reductive pathway is catalyzed by aldehyde oxidase, while 2 other less prominent oxidative pathways are catalyzed by CYP3A4. Ziprasidone is unlikely to interact with other medications metabolized by CYP3A4 since only 1/3 of the antipsychotic is metabolized by the CYP3A4 system. There are 12 identified ziprasidone metabolites (abbreviations italicized): Ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid ( OX-COOH ), OX-COOH glucuronide, 3-(piperazine-1-yl)-1,2-benzisothiazole ( BITP ), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-Methyl-dihydro-ziprasidone, S-Methyl-dihydro-ziprasidone-sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one ( OX-P ), and dihydro-ziprasidone-sulfone. As suggested by the quantity of metabolites, ziprasidone is metabolized through several different pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, and oxidative N-dealkylation of ziprasidone produces OX-COOH and BITP. OX-COOH undergoes phase II metabolism to yield a glucuronidated metabolite while BITP is sequentially oxidized into BITP sulfoxide, BITP sulfone, then BITP sulfone lactam. Ziprasidone can also undergo reductive cleavage and methylation to produce S-Methyl-dihydro-ziprasidone and then further oxidation to produce S-Methyl-dihydro-ziprasidone-sulfoxide. Finally dearylation of ziprasidone produces OX-P, and the process of hydration and oxidation transforms the parent drug into dihydro-ziprasidone-sulfone. Although CYP3A4 and aldehyde oxidase are the primary enzymes involved in ziprasidone metabolism, the pathways associated with each enzyme have not been specified. 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): Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as 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 half life of ziprasidone is 6-7 hours. Clearance (Drug A): No clearance available Clearance (Drug B): The mean apparent systemic clearance is 7.5 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): The most common adverse reactions reported with ziprasidone include somnolence, respiratory tract infections, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting, headache and nausea. Brand Names (Drug A): Suprefact Brand Names (Drug B): Geodon, Zeldox 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): Ziprasidone is an atypical antipsychotic used to manage schizophrenia, bipolar mania, and agitation in patients with schizophrenia.

Major

How do Buserelin and Zonisamide interact?

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.

How severe is the interaction between Buserelin and Zonisamide?

Minor

Is there an interaction between Buserelin and Zuclopenthixol?

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.

What is the severity of the interaction when Buserelin and Zuclopenthixol are co-administered?

Moderate

Can Buspirone and Abacavir be taken together?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

What is the severity of the interaction when Buspirone and Abacavir are co-administered?

Minor

Can Buspirone and Abametapir be taken together?

_In vitro_ studies suggest that abametapir's major circulating metabolite, abametapir carboxyl, is a potential inhibitor of CYP3A4, CYP2B6, and CYP1A2. 1 Despite being applied topically, serum concentrations of abametapir's carboxyl metabolite are generally high (greater than the parent drug) and prolonged due to exceedingly slow elimination. The estimated half-life of abametapir carboxyl in adults is 71 ± 40 hours or longer. The co-administration of substrates of CYPs 3A4, 2B6, or 1A2 with abametapir carboxyl may therefore result in supratherapeutic serum concentrations of the substrate in question due to an inhibition of its metabolism, which may increase the incidence and/or severity of serious adverse effects.

What is the severity of the interaction when Buspirone and Abametapir are co-administered?

Major

Do Buspirone and Abatacept interact with each other?

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates.

What is the severity of the interaction when Buspirone and Abatacept are co-administered?

Moderate

Is there an interaction between Buspirone and Abiraterone?

The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased risk and severity of adverse effects.

What is the severity of the interaction when Buspirone and Abiraterone are co-administered?

Moderate

Do Buspirone and Acalabrutinib interact with each other?

The subject drug is a weak CYP3A5 enzyme inhibitor, and the affected drug is metabolized by the CYP3A5 enzyme. Concomitant administration of these agents will decrease the metabolism of the CYP3A5 substrate (affected drug), increasing the serum concentration and therapeutic effect.

What is the risk level of combining Buspirone and Acalabrutinib?

Minor

Is there an interaction between Buspirone and Acebutolol?

The subject drug is known to be an inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to a decrease in metabolism by CYP2D6, which may result in increased incidence and/or severity of adverse effects related to the affected drug.

What is the severity of the interaction when Buspirone and Acebutolol are co-administered?

Moderate

Is there an interaction between Buspirone and Aceclofenac?

Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. Indication (Drug B): Aceclofenac is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. Pharmacodynamics (Drug B): Aceclofenac is a NSAID that inhibits both isoforms of COX enzyme, a key enzyme involved in the inflammatory cascade. COX-1 enzyme is a constitutive enzyme involved in prostacyclin production and protective functions of gastric mucosa whereas COX-2 is an inducible enzyme involved in the production of inflammatory mediators in response to inflammatory stimuli. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0.77uM) than COX-1 (IC50 of >100uM), which promotes its gastric tolerance compared to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also minimally inhibits COX-2 with IC50 value of 36uM. Although the mode of action of aceclofenac is thought to mainly arise from the inhibition of synthesis of prostaglandins (PGE2), aceclofenac also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factors (TNF). It is also reported that aceclofenac also affects the cell adhesion molecules from neutrophils. Aceclofenac also targets the synthesis of glycosaminoglycan and mediates chrondroprotective effects. Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. Mechanism of action (Drug B): Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac. Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes. In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes. Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity. The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes. Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. Absorption (Drug B): Aceclofenac is rapidly and completely absorbed from the gastrointestinal tract and circulates mainly as unchanged drug following oral administration. Peak plasma concentrations are reached around 1.25 to 3 hours post-ingestion, and the drug penetrates into the synovial fluid where the concentration may reach up to 60% of that in the plasma. There is no accumulation in regular dosing, with similar maximum plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) after single and multiple doses. Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. Volume of distribution (Drug B): The volume of distribution is approximately 25 L. Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. Protein binding (Drug B): It is reported to be highly protein-bound (>99%). Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. Metabolism (Drug B): 4'-hydroxyaceclofenac is the main metabolite detected in plasma however other minor metabolites include diclofenac, 5-hydroxyaceclofenac, 5-hydroxydiclofenac, and 4'-hydroxydiclofenac. It is probable that the metabolism of aceclofenac is mediated by CYP2C9. Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. Route of elimination (Drug B): The main route of elimination is via the urine where the elimination accounts for 70-80% of clearance of the drug. Approximately two thirds of the administered dose is excreted via the urine, mainly as glucuronidated and hydroxylated forms of aceclofenac. About 20% of the dose is excreted into feces. Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. Half-life (Drug B): The mean plasma elimination half-life is approximately 4 hours. Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. Clearance (Drug B): The mean clearance rate is approximately 5 L/h. Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. Toxicity (Drug B): Some common adverse effects include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness. Oral LD50 value in rats is 130 mg/kg. Brand Names (Drug A): Buspar Brand Names (Drug B): No brand names available Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum Synonyms (Drug B): Aceclofenac Acéclofénac Aceclofenac betadex Aceclofenaco Aceclofenacum Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. Summary (Drug B): No summary available

Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity.

What is the severity of the interaction when Buspirone and Aceclofenac are co-administered?

Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. Indication (Drug B): Aceclofenac is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. Pharmacodynamics (Drug B): Aceclofenac is a NSAID that inhibits both isoforms of COX enzyme, a key enzyme involved in the inflammatory cascade. COX-1 enzyme is a constitutive enzyme involved in prostacyclin production and protective functions of gastric mucosa whereas COX-2 is an inducible enzyme involved in the production of inflammatory mediators in response to inflammatory stimuli. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0.77uM) than COX-1 (IC50 of >100uM), which promotes its gastric tolerance compared to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also minimally inhibits COX-2 with IC50 value of 36uM. Although the mode of action of aceclofenac is thought to mainly arise from the inhibition of synthesis of prostaglandins (PGE2), aceclofenac also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factors (TNF). It is also reported that aceclofenac also affects the cell adhesion molecules from neutrophils. Aceclofenac also targets the synthesis of glycosaminoglycan and mediates chrondroprotective effects. Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. Mechanism of action (Drug B): Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac. Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes. In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes. Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity. The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes. Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. Absorption (Drug B): Aceclofenac is rapidly and completely absorbed from the gastrointestinal tract and circulates mainly as unchanged drug following oral administration. Peak plasma concentrations are reached around 1.25 to 3 hours post-ingestion, and the drug penetrates into the synovial fluid where the concentration may reach up to 60% of that in the plasma. There is no accumulation in regular dosing, with similar maximum plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) after single and multiple doses. Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. Volume of distribution (Drug B): The volume of distribution is approximately 25 L. Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. Protein binding (Drug B): It is reported to be highly protein-bound (>99%). Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. Metabolism (Drug B): 4'-hydroxyaceclofenac is the main metabolite detected in plasma however other minor metabolites include diclofenac, 5-hydroxyaceclofenac, 5-hydroxydiclofenac, and 4'-hydroxydiclofenac. It is probable that the metabolism of aceclofenac is mediated by CYP2C9. Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. Route of elimination (Drug B): The main route of elimination is via the urine where the elimination accounts for 70-80% of clearance of the drug. Approximately two thirds of the administered dose is excreted via the urine, mainly as glucuronidated and hydroxylated forms of aceclofenac. About 20% of the dose is excreted into feces. Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. Half-life (Drug B): The mean plasma elimination half-life is approximately 4 hours. Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. Clearance (Drug B): The mean clearance rate is approximately 5 L/h. Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. Toxicity (Drug B): Some common adverse effects include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness. Oral LD50 value in rats is 130 mg/kg. Brand Names (Drug A): Buspar Brand Names (Drug B): No brand names available Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum Synonyms (Drug B): Aceclofenac Acéclofénac Aceclofenac betadex Aceclofenaco Aceclofenacum Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. Summary (Drug B): No summary available

Minor

How do Buspirone and Acemetacin interact?

Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity.

What is the severity of the interaction when Buspirone and Acemetacin are co-administered?

Minor

Can Buspirone and Acenocoumarol be taken together?

Antidepressants are known to increase the risk of bleeding and bruising and this effect is especially important when taken concomitantly with vitamin K antagonists. The mechanism of action of this interaction has not been clearly established but it is thought to be related to the impairment of platelet aggregation, depletion of serotonin levels, and reduction of platelet count.

What is the severity of the interaction when Buspirone and Acenocoumarol are co-administered?

Minor

Can Buspirone and Acetaminophen be taken together?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

What is the risk level of combining Buspirone and Acetaminophen?

Minor

Can Buspirone and Acetazolamide be taken together?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

What is the severity of the interaction when Buspirone and Acetazolamide are co-administered?

Moderate

Is there an interaction between Buspirone and Acetylsalicylic acid?

Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity.

What is the severity of the interaction when Buspirone and Acetylsalicylic acid are co-administered?

Minor

Can Buspirone and Aclidinium be taken together?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Rate the interaction severity between Buspirone and Aclidinium.

Minor

Do Buspirone and Acyclovir interact with each other?

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

How severe is the interaction between Buspirone and Acyclovir?

Minor

Is there an interaction between Buspirone and Adagrasib?

Adagrasib is a CYP3A4 inhibitor; therefore, the concomitant use of adagrasib and sensitive CYP3A4 substrates increases the concentration of sensitive CYP3A4 substrates. This may increase the risk of adverse reactions related to these substrates.

What is the risk level of combining Buspirone and Adagrasib?

Major

Do Buspirone and Adalimumab interact with each other?

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates.

Rate the interaction severity between Buspirone and Adalimumab.

Moderate

Is there an interaction between Buspirone and Adefovir dipivoxil?

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

What is the risk level of combining Buspirone and Adefovir dipivoxil?

Minor

Can Buspirone and Agomelatine be taken together?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Rate the interaction severity between Buspirone and Agomelatine.

Moderate

Can Buspirone and Albutrepenonacog alfa be taken together?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

What is the severity of the interaction when Buspirone and Albutrepenonacog alfa are co-administered?

Minor

Do Buspirone and Aldesleukin interact with each other?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

What is the risk level of combining Buspirone and Aldesleukin?

Minor

How do Buspirone and Alfentanil interact?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

What is the risk level of combining Buspirone and Alfentanil?

Moderate

Is there an interaction between Buspirone and Alimemazine?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

How severe is the interaction between Buspirone and Alimemazine?

Moderate

Can Buspirone and Aliskiren be taken together?

Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. Indication (Drug B): Aliskiren is used for the treatment of hypertension in children above 6 years and adults. This drug may also be used in conjunction with antihypertensives such as calcium channel blockers and thiazides in products form to provide additional blood pressure control. Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. Pharmacodynamics (Drug B): Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke and myocardial infarction. Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. Mechanism of action (Drug B): Aliskiren is a renin inhibitor. Renin is secreted by the kidneys when blood volume and renal perfusion decrease. It normally cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II, an active protein. Angiotensin II is a potent vasoconstrictor that causes the release of catecholamines into the circulation. It also promotes the secretion of aldosterone in addition to sodium reabsorption, increasing blood pressure. Additionally, angiotensin II acts on the adrenal cortex where it stimulates aldosterone release. Aldosterone increases sodium reabsorption and potassium excretion in the nephron. Aliskiren prevents the above process via binding to renin at its active site, stopping the cleavage of angiotensin, in turn inhibiting the formation of angiotensin I. This ends the cascade of angiotensin II mediated mechanisms that normally increase blood pressure. Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. Absorption (Drug B): Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration. Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. Volume of distribution (Drug B): Unchanged aliskiren accounts for about 80% of the drug found in the plasma. Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. Protein binding (Drug B): The plasma protein binding of aliskiren ranges from 47-51%. Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. Metabolism (Drug B): About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma. Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. Route of elimination (Drug B): Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route. Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. Half-life (Drug B): Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours. Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. Clearance (Drug B): Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers. Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. Toxicity (Drug B): The oral LD50 of aliskiren in rats is >2000 mg/kg. Overdose information is limited in the literature, however, an overdose with aliskiren is likely to result in hypotension. Supportive treatment should be initiated in the case of an overdose. Brand Names (Drug A): Buspar Brand Names (Drug B): Rasilez, Tekturna, Tekturna Hct Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum Synonyms (Drug B): No synonyms listed Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. Summary (Drug B): Aliskiren is a direct renin inhibitor used to manage hypertension.

The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents.

What is the risk level of combining Buspirone and Aliskiren?

Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. Indication (Drug B): Aliskiren is used for the treatment of hypertension in children above 6 years and adults. This drug may also be used in conjunction with antihypertensives such as calcium channel blockers and thiazides in products form to provide additional blood pressure control. Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. Pharmacodynamics (Drug B): Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke and myocardial infarction. Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. Mechanism of action (Drug B): Aliskiren is a renin inhibitor. Renin is secreted by the kidneys when blood volume and renal perfusion decrease. It normally cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II, an active protein. Angiotensin II is a potent vasoconstrictor that causes the release of catecholamines into the circulation. It also promotes the secretion of aldosterone in addition to sodium reabsorption, increasing blood pressure. Additionally, angiotensin II acts on the adrenal cortex where it stimulates aldosterone release. Aldosterone increases sodium reabsorption and potassium excretion in the nephron. Aliskiren prevents the above process via binding to renin at its active site, stopping the cleavage of angiotensin, in turn inhibiting the formation of angiotensin I. This ends the cascade of angiotensin II mediated mechanisms that normally increase blood pressure. Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. Absorption (Drug B): Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration. Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. Volume of distribution (Drug B): Unchanged aliskiren accounts for about 80% of the drug found in the plasma. Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. Protein binding (Drug B): The plasma protein binding of aliskiren ranges from 47-51%. Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. Metabolism (Drug B): About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma. Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. Route of elimination (Drug B): Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route. Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. Half-life (Drug B): Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours. Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. Clearance (Drug B): Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers. Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. Toxicity (Drug B): The oral LD50 of aliskiren in rats is >2000 mg/kg. Overdose information is limited in the literature, however, an overdose with aliskiren is likely to result in hypotension. Supportive treatment should be initiated in the case of an overdose. Brand Names (Drug A): Buspar Brand Names (Drug B): Rasilez, Tekturna, Tekturna Hct Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum Synonyms (Drug B): No synonyms listed Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. Summary (Drug B): Aliskiren is a direct renin inhibitor used to manage hypertension.

Minor

How do Buspirone and Allopurinol interact?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

What is the severity of the interaction when Buspirone and Allopurinol are co-administered?

Minor

Can Buspirone and Almotriptan be taken together?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

What is the risk level of combining Buspirone and Almotriptan?

Moderate

Is there an interaction between Buspirone and Alogliptin?

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

What is the risk level of combining Buspirone and Alogliptin?

Minor

Is there an interaction between Buspirone and Alosetron?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Rate the interaction severity between Buspirone and Alosetron.

Moderate

Do Buspirone and Alprazolam interact with each other?

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

What is the risk level of combining Buspirone and Alprazolam?

Moderate