Drug Interactions between Kisqali Femara Co-Pack and Posicor

GENERALLY AVOID: Coadministration with potent CYP450 3A4 inhibitors may increase the plasma concentrations and the risk of adverse effects of ribociclib, which is a substrate of the isoenzyme. In healthy subjects, administration of a single 400 mg dose of ribociclib with ritonavir (100 mg twice daily for 14 days), a potent CYP450 3A4 inhibitor, resulted in a 1.7-fold and 3.2-fold increase in ribociclib peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to ribociclib administered alone. In addition, administration of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase ribociclib Cmax and AUC by 1.3-fold and 1.9-fold, respectively. The risk of adverse effects such as infections, neutropenia, leucopenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, anorexia, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Concomitant use of ribociclib with potent CYP450 3A4 inhibitors should generally be avoided. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. If no alternatives exist, the dose of ribociclib should be reduced to 400 mg once daily. Patients receiving concomitant treatment with a CYP450 3A4 inhibitor should be monitored for the development of ribociclib-related adverse effects. Following discontinuation of the potent CYP450 3A4 inhibitor, the ribociclib dosage should be returned (after at least 5 half-lives of the inhibitor) to that used prior to initiation of the inhibitor.

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MONITOR: Based on in vitro inhibition data, coadministration with mibefradil may increase the plasma concentrations of drugs that are substrates of CYP450 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by mibefradil.

MANAGEMENT: Caution is advised when mibefradil is used concomitantly with drugs that undergo metabolism by CYP450 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mibefradil is added to or withdrawn from therapy.

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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.

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