Drug Interactions between amoxicillin / clarithromycin / lansoprazole 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 clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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.