Drug Interactions between amoxicillin / clarithromycin / omeprazole and maraviroc

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of maraviroc, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of maraviroc (100 mg twice a day) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once a day) increased the mean maraviroc peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 3.5- and 5-fold, respectively, compared to administration alone. When the same dosage of maraviroc was administered with ritonavir (100 mg twice a day), maraviroc Cmax increased by nearly 1.3-fold and AUC by 2.6-fold. An even greater increase of nearly 5-fold in Cmax and 10-fold in AUC was observed during coadministration of maraviroc and saquinavir/ritonavir (1000 mg/100 mg twice a day). At 300 mg twice a day, mean maraviroc Cmax increased by approximately 2-fold and AUC by 3.6-fold during coadministration with atazanavir (400 mg once a day). When the same dosage of maraviroc was given with atazanavir/ritonavir (300 mg/100 mg once a day), maraviroc Cmax increased by 2.7-fold and AUC increased by nearly 5-fold. During coadministration with lopinavir/ritonavir (400 mg/100 mg twice a day), maraviroc Cmax and AUC increased by 2-fold and 4-fold, respectively. In patients with hepatic impairment, plasma drug concentrations are higher when maraviroc 150 mg is administered with a potent CYP450 3A4 inhibitor than when maraviroc 300 mg (normally recommended dose) is administered without a CYP450 3A4 inhibitor.

CONTRAINDICATED: Patients with severe renal impairment or end-stage renal disease (CrCl <30 mL/min) given maraviroc in combination with potent CYP450 3A4 inhibitors may have an increased risk of postural hypotension due to increased maraviroc exposure. Moreover, these patients often have cardiovascular comorbidities that could predispose them to adverse cardiovascular events triggered by postural hypotension. No studies have been performed in subjects with severe renal impairment or ESRD co-treated with maraviroc and potent CYP450 3A4 inhibitors. Hence, no dosage recommendation for maraviroc is available for these patients.

MANAGEMENT: Maraviroc should be administered at a dosage of 150 mg twice daily during coadministration with potent CYP450 3A4 inhibitors, including most protease inhibitors except tipranavir plus ritonavir. This dosage is recommended whether or not a concomitant CYP450 3A4 inducer (e.g., efavirenz, rifampin, carbamazepine, phenobarbital, phenytoin) is given. Patients with moderate hepatic impairment who receive 150 mg with a potent CYP450 3A4 inhibitor should be monitored closely for maraviroc-associated adverse events. Maraviroc is contraindicated for use in combination with potent CYP450 3A4 inhibitors in patients with severe renal impairment or end-stage renal disease (CrCl <30 mL/min).

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.