Drug Interactions between ceritinib and zuranolone

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 enhances the oral bioavailability of zuranolone. When administered with a low-fat meal (e.g., 400 to 500 calories, 25% fat), zuranolone peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.5- and 1.8-fold, respectively, compared to administration under fasted conditions. Zuranolone was administered with food in the premarketing study population. The efficacy of zuranolone when administered in the fasted state is unknown.

GENERALLY AVOID: Concomitant use of zuranolone with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence, confusion, dizziness, and gait disturbance.

MANAGEMENT: Zuranolone must be administered with fat-containing food (e.g., 400 to 1,000 calories, 25% to 50% fat) according to the manufacturer. Patients should also be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until at least 12 hours after administration of zuranolone.