Drug Interaction Report

MONITOR: Coadministration with olaparib may decrease the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 1A2 and/or 2B6. The proposed mechanism, based on in vitro data, is increased clearance due to olaparib-mediated induction of CYP450 1A2 and/or 2B6.

MANAGEMENT: Caution is advised if olaparib is used concomitantly with drugs that are substrates of CYP450 1A2 and/or 2B6. Pharmacologic response and serum levels should be monitored more closely whenever olaparib is added to or withdrawn from therapy with these drugs. Dosage adjustments may be required if an interaction is suspected.

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.