Drug Interactions between Ofev and omaveloxolone

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of nintedanib. After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions. Absorption was also delayed, as indicated by an increase in the median time to reach maximum plasma concentration (Tmax) from 2 hours in the fasted state to approximately 4 hours under fed conditions, irrespective of the type of food ingested. In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on their pharmaceutical quality, but swelling and deformation of the capsules were observed with longer exposure time due to water uptake of the gelatin capsule shell. Therefore, administration with soft food would not be expected to alter the clinical effect of nintedanib when taken immediately.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of nintedanib, which has been shown to be a substrate of the P-glycoprotein (P-gp) efflux transporter and a minor substrate of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of both P-gp-mediated efflux in the gut wall as well as CYP450 3A4-mediated first-pass metabolism in the intestinal tract by certain compounds present in grapefruit.

MANAGEMENT: Nintedanib should be administered with food to reduce the incidence of gastrointestinal effects. Nintedanib capsules may be taken with water or a small amount (teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding, and must be swallowed whole (unchewed) immediately, to ensure the capsule stays intact. Food containing grapefruit, grapefruit juice, Seville orange (a citrus relative of the grapefruit), or Seville orange juice should be avoided during treatment with nintedanib.

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.