Drug Interaction Report

MONITOR: Based on in vitro inhibition data, coadministration with olaparib may increase the plasma concentrations of drugs that are substrates of CYP450 3A4 (e.g., cyclosporine, cisapride, ergot alkaloids, fentanyl, lovastatin, oral midazolam, pimozide, quetiapine, simvastatin, sirolimus, tacrolimus, triazolam, vinca alkaloids), P-glycoprotein (P-gp) (e.g., colchicine, dabigatran, digoxin, lovastatin, pravastatin, simvastatin, sirolimus, tacrolimus), breast cancer resistance protein (BCRP) (e.g., methotrexate, rosuvastatin), organic anion transporting polypeptide 1B1 (OATP1B1) (e.g., bosentan, eluxadoline, glyburide, repaglinide, statins, valsartan), organic cation transporter 1 or 2 (OCT1, OCT2) (e.g., amantadine, metformin), organic anion transporter 3 (OAT3) (e.g., furosemide, methotrexate), and/or multidrug and toxin extrusion transporter 1 or 2K (MATE1, MATE-2K) (e.g., amantadine, metformin).

MANAGEMENT: Caution is advised when olaparib is used concomitantly with drugs that are substrates of the affected enzymes or transporters, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever olaparib is added to or withdrawn from therapy.

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.

ADJUST DOSING INTERVAL: Food reduces the oral bioavailability of betrixaban. When administered with a low-fat (900 calories; 20% fat) or high-fat (900 calories; 60% fat) meal, betrixaban peak plasma concentration (Cmax) and systemic exposure (AUC) decreased relative to administration in the fasting state by an average of 70% and 61%, respectively, with the low-fat meal and 50% and 48%, respectively, with the high-fat meal. The effect of food on betrixaban pharmacokinetics could be observed for up to 6 hours after meal intake.

MANAGEMENT: The manufacturer recommends taking betrixaban at the same time each day with food.