Drug Interaction Report

MONITOR: Coadministration with inhibitors of the organic cation 2 (OCT2) or multidrug and toxin extrusion 1 (MATE1) transporters may theoretically increase the plasma concentrations of tipiracil, an in vitro substrate of these transporters. Tipiracil is a thymidine phosphorylase inhibitor and is administered in combination with the antineoplastic thymidine-based nucleoside analog, trifluridine, to increase the systemic exposure of trifluridine. Increased levels of tipiracil may therefore further increase the systemic exposure of trifluridine, and the risk of adverse effects such as myelosuppression and gastrointestinal toxicity.

MANAGEMENT: Although the clinical significance is unknown, caution is advised if the combination of tipiracil and trifluridine is used concomitantly with drugs that are inhibitors of OCT2 and/or MATE1. Patients should be monitored for adverse effects including excessive bone marrow suppression and gastrointestinal toxicity. Patients should be advised to contact their physician if they develop signs and symptoms of myelosuppression such as pallor, dizziness, fatigue, lethargy, fainting, easy bruising or bleeding, or signs of infection such as fever, chills, sore throat, body aches, and other influenza-like symptoms.

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.

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.