Drug Interaction Report

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp), uridine diphosphate glucuronosyltransferase (UGT) 1A1 or 2B7, and/or breast cancer resistance protein (BCRP) may increase the plasma levels and risk of adverse effects of binimetinib. The proposed mechanism involves the reduced metabolic clearance of binimetinib through inhibition of P-gp, UGT 1A1, UGT 2B7, and/or BCRP. The clinical significance of this interaction is unknown as no clinically relevant drug interactions have been demonstrated with binimetinib.

MANAGEMENT: Until further information is available, caution is recommended if binimetinib must be used concomitantly with P-gp, UGT 1A1, UGT 2B7, and/or BCRP inhibitors. Binimetinib should be monitored more closely whenever a P-gp, UGT 1A1, UGT 2B7, and/or BCRP inhibitor is added to or withdrawn from therapy, and the binimetinib dosage adjusted as necessary.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of olaparib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a drug interaction study with 57 patients, mean olaparib systemic exposure (AUC) was increased approximately 2.7-fold by the potent CYP450 3A4 inhibitor itraconazole. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that a moderate inhibitor (fluconazole) may increase the AUC of olaparib by 2.2-fold. The interaction has not been studied with grapefruit juice. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to olaparib may increase the risk of adverse effects such as hematologic toxicity, nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain or discomfort.

MANAGEMENT: Food containing grapefruit, grapefruit juice, Seville orange (a citrus relative of the grapefruit), or Seville orange juice should be avoided during treatment with olaparib. Some authorities also recommend avoiding starfruit (carambola) and pomegranate.