Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations of celecoxib, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of celecoxib should be considered.

MANAGEMENT: Clinical monitoring for altered effects of celecoxib is recommended following initiation or discontinuation of a CYP450 2C9 inhibitor. Dosage adjustments may be required if an interaction is suspected. Patients should be advised to notify their physician if they experience potential signs and symptoms of celecoxib toxicity such as abdominal pain, black or tarry stools, nausea, vomiting, lethargy, fluid retention, swelling of legs, and worsening heart failure.

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).