Drug Interactions between Kisqali Femara Co-Pack and omaveloxolone

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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: Omaveloxolone may decrease the plasma concentrations of drugs that are substrates of CYP450 2C8 and/or 3A4 via induction of these isoenzymes. The systemic exposure (AUC) of repaglinide, a CYP450 2C8 substrate, decreased by approximately 35%, and the AUC of midazolam, a CYP450 3A4 substrate, decreased by approximately 45%, when administered with omaveloxolone. Reduced effectiveness of the substrates may result.

MANAGEMENT: The potential for diminished pharmacologic effects of CYP450 2C8 and/or 3A4 substrates should be considered during coadministration with omaveloxolone. The prescribing information for the substrates should be consulted for any dosage adjustments that may be required.

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of omaveloxolone, which is primarily metabolized by the isoenzyme. When administered with itraconazole, a potent CYP450 3A4 inhibitor, omaveloxolone peak plasma concentration (Cmax) and systemic exposure (AUC) increased 3-fold and 4-fold, respectively. When administered with verapamil, a moderate CYP450 3A4 inhibitor, omaveloxolone Cmax and AUC increased approximately 1.25-fold each. Increased exposure to omaveloxolone may increase the risk of adverse reactions such as lipid abnormalities and increased aminotransferases and B-type natriuretic peptide (BNP).

MANAGEMENT: Coadministration of omaveloxolone with potent or moderate CYP450 3A4 inhibitors should be avoided. If concomitant use of a potent CYP450 3A4 inhibitor is unavoidable, reduce the omaveloxolone dose to 50 mg once daily, and if adverse reactions occur, coadministration should be discontinued. If concomitant use of a moderate CYP450 3A4 inhibitor is unavoidable, reduce the omaveloxolone dose to 100 mg once daily, and if adverse reactions occur, further reduce the dose to 50 mg once daily.