Drug Interactions between amoxicillin / clarithromycin / omeprazole and pirfenidone

MONITOR: Coadministration with moderate or potent inhibitors of CYP450 2C9, 2C19, 2D6, and/or 2E1 may increase the plasma concentrations of pirfenidone, especially when used in addition to a moderate or potent CYP450 1A2 inhibitor. Pirfenidone is primarily (70% to 80%) metabolized by CYP450 1A2, with minor contribution from CYP450 2C9, 2C19, 2D6, and 2E1. In 25 healthy nonsmokers and 25 smokers who were administered a single dose of pirfenidone with the potent CYP450 1A2 inhibitor fluvoxamine (50 mg at bedtime for 3 days; 50 mg twice a day for 3 days; then 50 mg in the morning and 100 mg at bedtime for 4 days), pirfenidone systemic exposure (AUC) increased approximately 4-fold in nonsmoking subjects and 7-fold in smoking subjects. Fluvoxamine also inhibits CYP450 2C9, 2C19 and 2D6, although the extent to which these effects contribute to the interaction has not been established. The interaction has not been studied with specific inhibitors of other isoenzymes involved in the metabolism of pirfenidone.

MANAGEMENT: Concomitant use of pirfenidone with moderate or potent inhibitors of CYP450 2C9, 2C19, 2D6, and/or 2E1 in addition to a moderate or potent inhibitor of CYP450 1A2 (e.g., certain fluoroquinolones, oral contraceptives, deferasirox, methoxsalen, mexiletine, thiabendazole, ticlopidine, zileuton) should be avoided. No particular precaution is necessary if pirfenidone and CYP450 2C9, 2C19, 2D6, and/or 2E1 inhibitors are coadministered without a moderate or potent CYP450 1A2 inhibitor. However, a prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may increase plasma concentrations and the risk of adverse effects of pirfenidone for at least 28 days after administration of rolapitant.

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.