Drug Interactions between Kisqali Femara Co-Pack and tepotinib

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of tepotinib, which may increase the incidence and severity of adverse reactions such as interstitial lung disease/pneumonitis, hepatotoxicity, edema, nausea, vomiting, diarrhea, constipation, and musculoskeletal pain. Tepotinib is a substrate of both CYP450 3A4 isoenzyme and P-gp efflux transporter. However, the effect of CYP450 3A4 or P-gp inhibitors on tepotinib has not been studied clinically.

MANAGEMENT: Caution is advised when tepotinib is used with inhibitors of CYP450 3A4 and/or P-gp. Patients should be monitored for increased adverse effects, and the tepotinib dosage adjusted as necessary.