Drug Interactions between letermovir and sirolimus

MONITOR CLOSELY: Coadministration with letermovir may significantly increase the plasma concentrations of sirolimus. The proposed mechanism is letermovir inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of sirolimus. Enhanced sirolimus oral bioavailability due to inhibition of intestinal P-glycoprotein (P-gp) efflux transporter may also contribute. According to the product labeling, sirolimus peak plasma concentration (Cmax), systemic exposure (AUC) and concentration at 24 hours postdose (C24hr) increased by an average of 2.8-, 3.4- and 3.2-fold, respectively, when a single 2 mg dose of sirolimus was coadministered with letermovir 480 mg orally once daily. An increased risk of nephrotoxicity, as well as other adverse effects associated with sirolimus such as malignancies, infections, angioedema, fluid retention, interstitial lung disease (e.g., pneumonitis, bronchiolitis obliterans organizing pneumonia, pulmonary fibrosis), diabetes, hyperlipidemia and hypertension, may occur. Additional use of cyclosporine is likely to further increase the magnitude of interaction, since it is an inhibitor of CYP450 3A4 and a strong inhibitor of P-gp.

MANAGEMENT: Caution is advised when sirolimus is used with letermovir. Sirolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of letermovir. When letermovir is coadministered with cyclosporine, please refer to the sirolimus prescribing information for specific sirolimus dosing recommendations. Patients should be advised to seek medical attention if they experience adverse effects such as fever, infection, diarrhea, stomatitis, decreased urination, angioedema, peripheral edema, shortness of breath, difficulty breathing, and changes in motor function or mental status.