Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of sonidegib, which is primarily metabolized by the isoenzyme. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that sonidegib steady-state systemic exposure (AUC) would increase approximately 1.8-fold when sonidegib 200 mg once daily is coadministered with the moderate CYP450 3A4 inhibitor erythromycin for 14 days, and 2.8-fold when coadministered with erythromycin for 4 months.

MANAGEMENT: Concomitant use of sonidegib with moderate CYP450 3A4 inhibitors should generally be avoided. If coadministration is required, the manufacturer recommends limiting use of the moderate CYP450 3A4 inhibitor to less than 14 days and monitoring for adverse reactions, particularly musculoskeletal toxicity.

ADJUST DOSING INTERVAL: Food significantly increases the oral bioavailability of sonidegib. According to the product labeling, administration of sonidegib with a high-fat meal (approximately 1000 calories; 50% from fat) increased mean sonidegib peak plasma concentration (Cmax) and systemic exposure (AUC) by 7.4- to 7.8-fold.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of sonidegib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. 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 sonidegib may increase the risk of adverse effects such as musculoskeletal toxicity, fatigue, nausea, vomiting, diarrhea, anorexia, weight loss, alopecia, pruritus, and dysgeusia.

MANAGEMENT: Sonidegib should be administered on an empty stomach, at least 1 hour before or 2 hours after a meal. Patients should avoid consumption of grapefruit or grapefruit juice during treatment with sonidegib.