Drug Interactions between avacopan and Kisqali Femara Co-Pack

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 avacopan may increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 3A4 isoenzyme. The mechanism is reduced clearance due to inhibition of CYP450 3A4 by avacopan. The interaction may be particularly important for sensitive substrates or those that demonstrate a narrow therapeutic index. When midazolam, a sensitive CYP450 3A4 substrate, was administered with avacopan dosed at 30 mg twice daily for 11 days under fasted condition, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 55% and 81%, respectively. These results suggest weak inhibition of CYP450 3A4 by avacopan.

MANAGEMENT: Caution is advised when avacopan is used concomitantly with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever avacopan is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a weak CYP450 3A4 inhibitor like avacopan and for any dosage adjustments that may be required.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of avacopan. CYP450 3A4 is the primary enzyme responsible for the clearance of avacopan and for the formation and clearance of the major circulating metabolite M1, a mono-hydroxylated metabolite with similar pharmacologic activity as avacopan on the complement 5a receptor (C5aR). When avacopan was administered with the potent CYP450 3A4 inhibitor, itraconazole (200 mg once daily for 4 days), avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.9-fold and 2.2-fold, respectively. The Cmax and AUC of M1 were not significantly altered. The interaction has not been studied with other, less potent inhibitors.

MANAGEMENT: Caution is advised when avacopan is used with CYP450 3A4 inhibitors. Patients should be monitored for serious adverse reactions such as hepatotoxicity and infections.