Drug Interactions between Kisqali Femara Co-Pack and repotrectinib

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of repotrectinib. According to prescribing information, repotrectinib is primarily metabolized by CYP450 3A4, and is also a substrate of P-glycoprotein (P-gp) in vitro. Drug interaction studies have shown that administration of repotrectinib with itraconazole, a combined potent CYP450 3A4 and P-gp inhibitor, increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of repotrectinib by 1.7-fold and 5.9-fold, respectively. Increased exposure to repotrectinib may increase the risk of adverse reactions such as dizziness, fatigue, cognitive disorders, ataxia, dysgeusia, peripheral neuropathy, muscular weakness, and dyspnea as well as more serious adverse effects such as interstitial lung disease/pneumonitis, liver transaminase elevations, myalgia with creatinine phosphokinase (CPK) elevation, hyperuricemia, and skeletal fractures.

MANAGEMENT: Coadministration of repotrectinib with potent or moderate CYP450 3A4 inhibitors should generally be avoided. According to product labeling, moderate and potent CYP450 3A4 inhibitors should be discontinued for 3 to 5 elimination half-lives prior to starting repotrectinib.

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 repotrectinib, a moderate CYP450 3A4 inducer, may decrease the plasma concentrations and therapeutic efficacy of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is increased clearance due to induction of CYP450 3A4 activity by repotrectinib. When midazolam, a probe substrate for CYP450 3A4, was administered following treatment with repotrectinib (160 mg once daily for 14 days followed by 160 mg twice daily for 7 days), midazolam systemic exposure (AUC) and peak plasma concentration (Cmax) reduced by 69% and 48%, respectively.

MANAGEMENT: Caution is advised when repotrectinib is used concomitantly with drugs that are substrates of CYP450 3A4. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever repotrectinib is added to or withdrawn from therapy. Avoid concomitant use with repotrectinib where minimal decreases in concentration of the CYP450 3A4 substrate may lead to serious therapeutic failure. If coadministration is required, the CYP450 3A4 substrate dosage should be increased in accordance with approved product labeling.