Drug Interactions between Kisqali Femara Co-Pack and mirabegron

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 may increase the plasma concentrations of mirabegron, which has been shown in vitro to be a substrate of the isoenzyme. However, in vivo results indicate that CYP450 3A4 may play a limited role in the overall elimination. In a study consisting of 23 healthy male and female subjects, mirabegron peak plasma concentration (Cmax) increased by 45% and systemic exposure (AUC) increased by 80% when a single 100 mg dose of mirabegron was administered following multiple dosing of ketoconazole 400 mg daily for 9 days. No dosage adjustment is recommended when mirabegron is administered in combination with ketoconazole and probably other CYP450 3A4 inhibitors.