Drug Interactions between Kisqali Femara Co-Pack and mobocertinib

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of mobocertinib, which is primarily metabolized by the isoenzyme. Elevated plasma concentrations of mobocertinib may increase the risk for adverse effects such as QT prolongation, heart failure or reduced ejection fraction, cardiomyopathy, heart block, diarrhea, rash, stomatitis, fatigue, and musculoskeletal pain. The risk of QT prolongation in particular may be increased with concomitant use of moderate CYP450 3A4 inhibitors that are also known to prolong the QT interval (e.g., ciprofloxacin, crizotinib, dronedarone, erythromycin, fluconazole, ribociclib). Based on drug interaction studies using model-informed approaches, coadministration of mobocertinib with repeated doses of a moderate CYP450 3A4 inhibitor is predicted to increase the steady-state combined molar AUC (systemic exposure) of mobocertinib and its active metabolites by approximately 100% to 200%.

MANAGEMENT: Concomitant use of mobocertinib with moderate CYP450 3A4 inhibitors should be avoided when possible. If coadministration is required, the dosage of mobocertinib should be reduced by approximately 50% (from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg) and the QTc interval monitored more frequently with electrocardiograms, especially in patients treated with moderate CYP450 3A4 inhibitors that are also known to prolong the QT interval. Mobocertinib may be resumed at the previous dose after the moderate CYP450 3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives.

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.

GENERALLY AVOID: Coadministration with mobocertinib 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. The proposed mechanism is increased clearance due to mobocertinib-mediated induction of CYP450 3A4. Concomitant use of mobocertinib 160 mg once daily with oral or intravenous midazolam (a sensitive CYP450 3A4 substrate) decreased the midazolam systemic exposure (AUC) by 32% and 16%, respectively.

MANAGEMENT: Use of mobocertinib 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 required, patients should be monitored for diminished therapeutic effects. Clinical and laboratory monitoring should be considered whenever mobocertinib is added to or withdrawn from therapy with these drugs, and the dosage of the sensitive CYP450 3A4 substrate drug adjusted in accordance with the approved product label.