Drug Interaction Report

MONITOR: Coadministration with crizotinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by crizotinib. The interaction has been studied with midazolam, a probe substrate for CYP450 3A4. In study patients, administration of oral midazolam during treatment with crizotinib (250 mg twice daily for 28 days) resulted in a 3.7-fold increase in mean midazolam systemic exposure (AUC) compared to administration of midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP450 3A4.

MANAGEMENT: Caution is advised when crizotinib is used concomitantly with drugs that undergo metabolism by CYP450 3A4. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever crizotinib is added to or withdrawn from therapy. Concomitant use of crizotinib and substrates of CYP450 3A4 with a narrow therapeutic index (e.g., antiarrhythmic agents, benzodiazepines, ergot derivatives, immunosuppressants, vinca alkaloids) should be avoided if possible.

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 DOSE: Smoking tobacco may decrease the steady-state systemic exposure of istradefylline by 38% to 54%.

MANAGEMENT: The possibility of reduced therapeutic effects of istradefylline should be considered in smokers. The manufacturer recommends an istradefylline dosage of 40 mg once daily in patients who smoke 20 or more cigarettes (or the equivalent amount of another tobacco product) per day.