Drug Interaction Report

MONITOR: Coadministration with CYP450 3A4 and/or 2B6 inhibitors may increase plasma concentrations of thiotepa and decrease concentrations of its active metabolite triethylenephosphoramide (TEPA). Thiotepa is a prodrug that is primarily converted to TEPA by these isoenzymes. A pharmacokinetic study evaluating six breast cancer patients receiving high-dose chemotherapy (cyclophosphamide 1,500 mg/m2/day, thiotepa 120 mg/m2/day, and carboplatin AUC 5 mg min/mL/day) with the moderate CYP450 3A4 inhibitor aprepitant (125 mg one day before chemotherapy, then 80 mg daily during and for three days after) showed a 15% increase in total thiotepa exposure, a 33% decrease in TEPA formation, and 20% reduction in TEPA exposure.

MANAGEMENT: Caution and closer monitoring for decreased efficacy and adverse effects are advised when thiotepa is used concurrently with CYP450 3A4 and/or 2B6 inhibitors. Patients should be more closely monitored for thiotepa-related toxicities such as myelosuppression, cutaneous toxicity, and neurotoxicity.

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of orally administered ranolazine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

MANAGEMENT: Patients treated with ranolazine should avoid consumption of grapefruit juice and other grapefruit products if possible. Otherwise, the dosage of ranolazine should be limited to 500 mg twice a day.