Drug Interactions between brigatinib and Kisqali Femara Co-Pack

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of brigatinib, which is partially metabolized by the isoenzyme. When a single 90 mg dose of brigatinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg twice daily), brigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 21% and 101%, respectively, compared to brigatinib administered alone. Simulations from a physiologically-based pharmacokinetic model predict a moderate CYP450 3A4 inhibitor may increase the AUC of brigatinib by approximately 40%.

MANAGEMENT: Concomitant use of moderate CYP450 3A4 inhibitors should generally be avoided during therapy with brigatinib. If coadministration is required, the brigatinib dose should be reduced by approximately 40% (i.e., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). Some authorities state that no dose adjustment is required. However, patients should be monitored for increased brigatinib adverse reactions such as nausea, vomiting, diarrhea, hypertension, bradycardia, hyperglycemia, visual disturbances, lymphopenia, anemia, and elevations in pancreatic enzymes and creatine phosphokinase. If a dose adjustment is made, the brigatinib dose that was tolerated previously may be resumed following discontinuation of the CYP450 3A4 inhibitor.

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 brigatinib may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Brigatinib has been shown in vitro to induce CYP450 3A4 at clinically relevant plasma concentrations.

MANAGEMENT: Caution is advised when brigatinib is used concomitantly with medications 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 brigatinib is added to or withdrawn from therapy.