Drug Interactions between amoxicillin / clarithromycin / omeprazole and etravirine

GENERALLY AVOID: Coadministration with etravirine may decrease the plasma concentrations of clarithromycin and increase concentrations of the active metabolite, 14-hydroxy-clarithromycin. The mechanism is etravirine induction of CYP450 3A4, the isoenzyme that metabolizes clarithromycin to 14-hydroxy-clarithromycin. In 15 study subjects administered clarithromycin 500 mg twice a day with etravirine, clarithromycin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by 34%, 39% and 53%, respectively, while Cmax, AUC and Cmin of 14-hydroxy-clarithromycin increased by 33%, 21% and 5%, respectively. Etravirine Cmax, AUC, and Cmin also increased by over 40% each due to inhibition of its CYP450 3A4 metabolism by clarithromycin.

MANAGEMENT: Because 14-hydroxy-clarithromycin has demonstrated reduced activity relative to the parent drug against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered during coadministration of clarithromycin with etravirine. Therefore, alternatives to clarithromycin (e.g., azithromycin) should be considered for the treatment of MAC in patients receiving etravirine.

MONITOR: Coadministration of etravirine with a drug that is both a substrate as well as inhibitor of CYP450 2C19 and/or 2C9 may result in increased plasma concentrations of both drugs. Etravirine itself is also a substrate and inhibitor of CYP450 2C19 and 2C9. Theoretically, metabolism of etravirine and the coadministered drug may be mutually inhibited when used in combination. In 18 study subjects administered etravirine with the CYP450 2C19 inhibitor omeprazole (40 mg once a day), etravirine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 41%, respectively. The effect of etravirine on omeprazole pharmacokinetics was not reported.

MANAGEMENT: Because safety data regarding increased etravirine exposures are limited, caution is advised if etravirine is prescribed in combination with a CYP450 2C19 or 2C9 inhibitor. In addition, dosage adjustments may be required for the coadministered drug if it is also a substrate of CYP450 2C19 or 2C9.

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.