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.

ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.