Drug Interaction Report

MONITOR: Coadministration with other myelosuppressive agents may potentiate and prolong the bone marrow toxicity associated with olaparib. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported in patients treated with olaparib. The majority of cases were fatal, and the duration of therapy with olaparib in patients who developed secondary MDS/cancer-therapy related AML varied from less than 6 months to greater than 2 years. All patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents.

MANAGEMENT: Caution is advised if olaparib is prescribed with other myelosuppressive agents. Complete blood counts should be performed at baseline and monthly thereafter. Do not start olaparib until patients have recovered from hematologic toxicity caused by previous chemotherapy. For prolonged hematologic toxicities, olaparib should be interrupted and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, a haematologist should be consulted for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue olaparib. Patients should be advised to contact their physician if they experience weakness, fatigue, fever, weight loss, infections, shortness of breath, unusual bleeding or bruising, or blood in urine or stool.

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: Administration of trifluridine-tipiracil with a standardized high-fat, high-calorie meal has been shown to decrease trifluridine peak plasma concentration (Cmax) as well as tipiracil Cmax and systemic exposure (AUC) by approximately 40% compared to administration in a fasting state in patients with cancer given a single 35 mg/m2 dose. No change in trifluridine AUC was observed.

MANAGEMENT: Based on the observed correlation between increases in the Cmax of trifluridine and decreases in neutrophil counts, trifluridine-tipiracil should be taken within one hour after completion of the morning and evening meals.