Drug Interactions between amoxicillin / clarithromycin / omeprazole and flibanserin

CONTRAINDICATED: Coadministration with moderate and potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of flibanserin, which is primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 2C19. High plasma levels of flibanserin may increase the risk of severe hypotension, syncope, and central nervous system depression. In 15 healthy female subjects, administration of a single 100 mg dose of flibanserin following pretreatment with fluconazole (400 mg once, then 200 mg once daily for 5 days), a moderate CYP450 3A4 and potent CYP450 2C19 inhibitor, increased flibanserin peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.2- and 7-fold, respectively, compared to administration of flibanserin alone. Hypotension or syncope requiring therapeutic intervention (placement in supine position with legs elevated) occurred in 3 (20%) subjects given flibanserin and fluconazole, compared to no subject given flibanserin alone or fluconazole alone. One of the 3 subjects became unresponsive with a blood pressure of 64/41 mmHg and was taken to the hospital emergency department, where she required intravenous saline. In another study, flibanserin Cmax increased by 1.8-fold and AUC increased by 4.5-fold when a single 50 mg dose was administered to 24 healthy female subjects following pretreatment with ketoconazole (400 mg once daily for 5 days), a potent CYP450 3A4 inhibitor. Syncope occurred in 1 (4%) of 24 subjects receiving flibanserin and ketoconazole, 1 (4%) of 24 subjects receiving flibanserin alone, and no subject receiving ketoconazole alone. Likewise, when a single 50 mg dose of flibanserin was given to 12 healthy male and female subjects following pretreatment with itraconazole (400 mg once, then 200 mg once daily for 4 days), flibanserin Cmax and AUC increased by 1.7- and 2.6-fold, respectively. It should be noted that the 200 mg itraconazole dose does not maximally inhibit CYP450 3A4.

MANAGEMENT: Concomitant use of flibanserin with moderate or potent CYP450 3A4 inhibitors is considered contraindicated. When initiating flibanserin following treatment with a moderate or potent CYP450 3A4 inhibitor, the manufacturer recommends waiting until 2 weeks after the last dose of CYP450 3A4 inhibitor. Conversely, if a moderate or potent CYP450 3A4 inhibitor is required during flibanserin therapy, flibanserin should be discontinued at least 2 days before starting the CYP450 3A4 inhibitor. Close monitoring for signs of hypotension and syncope is advised if the CYP450 3A4 inhibitor is needed sooner.

MONITOR: Coadministration with inhibitors of CYP450 2C19 may increase the plasma concentrations of flibanserin, which is partially metabolized by the isoenzyme. High plasma levels of flibanserin may increase the risk of severe hypotension, syncope, and central nervous system depression. In a pharmacogenomic study where female subjects were given flibanserin 100 mg once daily, flibanserin peak plasma concentration (Cmax) and systemic exposure (AUC) were increased 1.5- and 1.3-fold, respectively, in the nine subjects who were poor metabolizers of CYP450 2C19 compared to the eight subjects who were extensive metabolizers. Flibanserin half-life was 13.5 hours in the poor metabolizers and 11.1 hours in the extensive metabolizers. Syncope occurred in one (11%) of the CYP450 2C19 poor metabolizers and none of the extensive metabolizers. Flibanserin AUC in this subject was 3.2 fold higher than in the CYP450 2C19 extensive metabolizers.

MANAGEMENT: Caution is advised when flibanserin is used with CYP450 2C19 inhibitors. Patients should be monitored for signs and symptoms of hypotension, syncope, and central nervous system depression.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.