Drug Interactions between amoxicillin / clarithromycin / omeprazole and omaveloxolone

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of omaveloxolone, which is primarily metabolized by the isoenzyme. When administered with itraconazole, a potent CYP450 3A4 inhibitor, omaveloxolone peak plasma concentration (Cmax) and systemic exposure (AUC) increased 3-fold and 4-fold, respectively. When administered with verapamil, a moderate CYP450 3A4 inhibitor, omaveloxolone Cmax and AUC increased approximately 1.25-fold each. Increased exposure to omaveloxolone may increase the risk of adverse reactions such as lipid abnormalities and increased aminotransferases and B-type natriuretic peptide (BNP).

MANAGEMENT: Coadministration of omaveloxolone with potent or moderate CYP450 3A4 inhibitors should be avoided. If concomitant use of a potent CYP450 3A4 inhibitor is unavoidable, reduce the omaveloxolone dose to 50 mg once daily, and if adverse reactions occur, coadministration should be discontinued. If concomitant use of a moderate CYP450 3A4 inhibitor is unavoidable, reduce the omaveloxolone dose to 100 mg once daily, and if adverse reactions occur, further reduce the dose to 50 mg once daily.

MONITOR: Omaveloxolone may decrease the plasma concentrations of drugs that are substrates of CYP450 2C8 and/or 3A4 via induction of these isoenzymes. The systemic exposure (AUC) of repaglinide, a CYP450 2C8 substrate, decreased by approximately 35%, and the AUC of midazolam, a CYP450 3A4 substrate, decreased by approximately 45%, when administered with omaveloxolone. Reduced effectiveness of the substrates may result.

MANAGEMENT: The potential for diminished pharmacologic effects of CYP450 2C8 and/or 3A4 substrates should be considered during coadministration with omaveloxolone. The prescribing information for the substrates should be consulted for any dosage adjustments that may be required.

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.