Drug Interaction Report

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of omaveloxolone, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. 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. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to omaveloxolone may increase the risk of adverse reactions such as lipid abnormalities and increased aminotransferases and B-type natriuretic peptide (BNP).

ADJUST DOSING INTERVAL: Food may increase the oral bioavailability of omaveloxolone. Coadministration with a high-fat meal (800 to 1000 calories, with approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively) increased omaveloxolone Cmax and AUC by approximately 350% and 15%, respectively, compared to fasted conditions.

MANAGEMENT: Omaveloxolone should be administered on an empty stomach at least 1 hour before eating. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with omaveloxolone.