Drug Interaction Report

GENERALLY AVOID: Crizotinib can cause bradycardia and may have additive effects with other drugs that also slow the heart rate. Bradycardia with a heart rate less than 50 beats per minute occurred in 10% to 14% of patients treated with crizotinib in two clinical studies.

MANAGEMENT: Concomitant use of crizotinib with other agents known to cause bradycardia such as beta-blockers, calcium channel blockers, cholinesterase inhibitors, clonidine, and digoxin should generally be avoided whenever possible. Otherwise, heart rate and blood pressure should be monitored closely. If Grade 2 or 3 symptomatic bradycardia occurs, crizotinib should be withheld, the use of concomitant medications re-evaluated, and the dosage of crizotinib adjusted accordingly. Crizotinib should be permanently discontinued for Grade 4 bradycardia. In patients who develop Grade 4 bradycardia associated with concomitant medications known to cause bradycardia or hypotension, crizotinib should be withheld until Grade 1 or less, and if concomitant medications can be discontinued, crizotinib may be restarted at 250 mg once daily with frequent monitoring.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of crizotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because crizotinib 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.

Food has no significant effect on the gastrointestinal absorption of crizotinib. According to the product labeling, a high-fat meal reduced crizotinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 14%.

MANAGEMENT: Patients treated with crizotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Crizotinib may be taken without regards to food.