Drug Interactions between darolutamide and Kisqali Femara Co-Pack

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of darolutamide, which is a substrate of both the isoenzyme and the efflux transporter. When darolutamide was coadministered with itraconazole, a dual P-gp and potent CYP450 3A4 inhibitor, mean darolutamide peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 40% and 70%, respectively, compared to administration of darolutamide alone. The interaction has not been studied with less potent inhibitors or lone inhibitors of CYP450 3A4 or P-gp. Caution is advised when darolutamide is used with CYP450 3A4 or P-gp inhibitors. Patients should be monitored more frequently for adverse effects such as fatigue, hypertension, neutropenia and abnormal liver function tests, and the darolutamide dosage adjusted as necessary in accordance with the product labeling.