Drug Interaction Report

GENERALLY AVOID: Coadministration with belzutifan may decrease the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 3A4. The interaction may be significant for sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index. In addition, the extent of the decrease in concentration and effects may be more pronounced in patients who are dual uridine diphosphate glucuronosyltransferase (UGT) 2B17 and CYP450 2C19 poor metabolizers. The proposed mechanism is increased clearance due to belzutifan-mediated induction of CYP450 3A4. Concomitant use of belzutifan (120 mg once daily) with midazolam (a sensitive CYP450 3A4 substrate) decreased the midazolam systemic exposure (AUC) and peak plasma concentration (Cmax) by 40% and 34%, respectively. In patients with higher belzutifan concentrations (e.g., dual UGT 2B17 and CYP450 2C19 poor metabolizers) the AUC of midazolam is predicted to decrease by up to 70%.

MANAGEMENT: Use of belzutifan with sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index (e.g., cisapride, ergot alkaloids, colchicine, fentanyl, macrolide immunosuppressants, midazolam, pimozide, triazolam, vinca alkaloids) should generally be avoided. If coadministration is unavoidable, patients should be monitored for diminished therapeutic effects. Clinical and laboratory monitoring should be considered whenever belzutifan is added to or withdrawn from therapy with these drugs, and the dosage of the sensitive CYP450 3A4 substrate drug adjusted as necessary.

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.