Drug Interactions between encorafenib and Kisqali Femara Co-Pack

GENERALLY AVOID: Coadministration of encorafenib with a drug that is both a substrate as well as a moderate inhibitor of CYP450 3A4 may result in increased plasma concentrations of encorafenib and significantly decreased plasma concentrations of the other drug. Encorafenib itself is a substrate and a potent inducer of CYP450 3A4. When a single 50 mg dose of encorafenib (equivalent to 0.1 times the recommended dose) was administered with diltiazem, a moderate CYP450 3A4 inhibitor, encorafenib peak plasma concentration (Cmax) increased by 45% and systemic exposure (AUC) increased by 2-fold. Increased exposure to encorafenib may increase the risk of serious and life-threatening adverse effects such as hemorrhage, uveitis, QT prolongation, hepatotoxicity, dermatologic reactions, and new malignancies. Conversely, administration of a single 2 mg dose of the sensitive CYP450 3A4 substrate midazolam after repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily resulted in decreased systemic exposure (AUC) and peak plasma concentration (Cmax) of midazolam by approximately 82% and 74%, respectively, compared to midazolam alone. Reduced plasma concentrations may potentially lead to decreased efficacy of the CYP450 3A4 substrate.

MANAGEMENT: Concomitant use of encorafenib with moderate CYP450 3A4 inhibitors that are also sensitive CYP450 3A4 substrates should generally be avoided. If coadministration is required, the manufacturer recommends reducing the encorafenib dose to one-half of the dose used prior to addition of the moderate CYP450 3A4 inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the encorafenib dose that was taken prior to initiating the inhibitor may be resumed. If the concomitant medication also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for any concomitant medication should be consulted for further guidance and assessment of benefits versus risks of coadministration, as well as any dosage adjustments that may be required during coadministration and/or following the discontinuation of the potent CYP450 3A4 inducer.

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.