Drug Interaction Report

MONITOR: Coadministration with ranolazine may increase the plasma concentrations of drugs that are substrates of the organic cation transporter 2 (OCT2). The proposed mechanism is inhibition of OCT2-mediated renal tubular secretion by ranolazine, resulting in decreased clearance of drugs that are eliminated by this pathway such as metformin. When metformin 1000 mg twice daily was administered concomitantly with ranolazine 500 mg and 1000 mg twice daily in subjects with type 2 diabetes mellitus, metformin systemic exposure (AUC) increased by 40% and 80%, respectively, compared to administration of metformin alone.

MANAGEMENT: It may be advisable to monitor for altered efficacy and safety when an OCT2 substrate is coadministered with ranolazine, particularly in the elderly and patients with renal impairment. A dosage adjustment of the OCT2 substrate may be required.

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.

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.