Drug Interaction Report

MONITOR CLOSELY: Coadministration with letermovir may significantly increase the plasma concentrations of tacrolimus. The proposed mechanism is letermovir inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of tacrolimus. According to the product labeling, tacrolimus peak plasma concentration (Cmax), systemic exposure (AUC) and concentration at 24 hours postdose (C24hr) increased by an average of 1.6-, 2.4- and 2.5-fold, respectively, when a single 5 mg dose of tacrolimus was coadministered with letermovir 480 mg orally once daily. An increased risk of nephro- and neurotoxicity, as well as other adverse effects associated with tacrolimus such as malignancies, infections, diabetes, hyperkalemia, hypertension and QT prolongation, may occur. Tacrolimus had no effect on the pharmacokinetics of letermovir.

MANAGEMENT: Caution is advised when tacrolimus is used with letermovir. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of letermovir. Patients should be advised to seek medical attention if they experience adverse effects such as fever, infection, diarrhea, tremor, decreased urination, headache, paresthesia, seizures, and changes in motor function, mental status, or sensory function.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.