Drug Interaction Report

MONITOR: Coadministration of cabozantinib with multidrug resistance-associated proteins (MRP2) inhibitors may increase exposure and toxicity of cabozantinib. In vitro studies have shown MRP2 inhibitors may increase the plasma concentrations of cabozantinib, a MRP2 substrate. The clinical relevance of this finding is not known.

MANAGEMENT: Caution is advised if cabozantinib is used concomitantly with a MRP2 inhibitor. Monitor for cabozantinib toxicity, such as gastrointestinal perforations and fistulas, hemorrhage, thrombotic events, hypertension, diarrhea, and palmar-plantar erythrodysesthesia. Dose reductions, interruption or discontinuation of cabozantinib may be necessary if toxicity occurs.

ADJUST DOSING INTERVAL: Food may alter the oral bioavailability of cabozantinib. When healthy subjects were given a single 140 mg oral dose with a high-fat meal, cabozantinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 41% and 57%, respectively, relative to administration under fasting conditions. In clinical studies, patients were administered cabozantinib without food.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of cabozantinib, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Cabozantinib should be administered at least one hour before or two hours after a meal. The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided.