Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of crizotinib, which is primarily metabolized by the isoenzyme. In study subjects, administration of a single 150 mg oral dose of crizotinib during treatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) resulted in an approximately 1.4-fold increase in crizotinib peak plasma concentration (Cmax) and 3.2-fold increase in systemic exposure (AUC) compared to crizotinib administered alone. The effect of CYP450 3A4 inhibitors on steady-state crizotinib exposure has not been evaluated. 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.

MANAGEMENT: Concomitant use of crizotinib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of crizotinib during and for 2 weeks after treatment with itraconazole.

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.