Drug Interactions between sonidegib and Zykadia

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ceritinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ceritinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death. Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ceritinib. The mechanism of interaction is unknown. Compared to the fast state, administration of a single 500 mg dose of ceritinib with a high-fat meal (approximately 1000 calories; 58 grams of fat) increased ceritinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 41% and 73%, respectively, and administration with a low-fat meal (approximately 330 calories; 9 grams of fat) increased ceritinib Cmax and AUC by 43% and 58%, respectively. A dose of 600 mg or higher taken with a meal is expected to produce systemic exposure exceeding that from a 750 mg dose taken in the fasted state, which may lead to increased adverse effects.

MANAGEMENT: Patients treated with ceritinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ceritinib should be administered on an empty stomach (i.e., avoid administration within 2 hours of a meal).

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.