Drug Interaction Report

MONITOR: Coadministration with tepotinib may increase the plasma concentrations and risk of adverse effects of drugs that are substrates of P-glycoprotein (P-gp). The proposed mechanism is decreased clearance due to tepotinib-mediated inhibition of P-gp efflux transport protein. Coadministration with tepotinib increased the peak plasma concentration (Cmax) and systemic exposure (AUC0-INF) of dabigatran (a P-gp substrate) by 40% and 50%, respectively.

MANAGEMENT: Caution is advised when tepotinib is used concomitantly with drugs that are substrates of P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever tepotinib is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. The prescribing information recommends avoiding concomitant use of tepotinib with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. When concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pazopanib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of pazopanib. The mechanism of interaction is unknown. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in peak plasma concentration (Cmax) and systemic exposure (AUC).

MANAGEMENT: Patients treated with pazopanib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Pazopanib should be administered at least one hour before or two hours after a meal.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of tepotinib. When tepotinib was administered after a high-fat, high-calorie meal (approximately 800 to 1000 calories; 150 calories from protein, 250 calories from carbohydrate, 500 to 600 calories from fat), tepotinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2-fold and 1.6-fold, respectively, compared to administration under fasted conditions.

MANAGEMENT: Tepotinib should be administered with food at approximately the same time each day.