Drug Interactions between emtricitabine / nelfinavir / tenofovir disoproxil and encorafenib

GENERALLY AVOID: Coadministration of encorafenib with a drug that is both a substrate as well as a potent inhibitor of CYP450 3A4 may result in significantly 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 posaconazole, a potent CYP450 3A4 inhibitor, encorafenib peak plasma concentration (Cmax) increased by 68% and systemic exposure (AUC) increased by 3-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 potent 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-third of the dose used prior to addition of the potent 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. In addition, patients should be monitored for reduced efficacy of the concomitant medication. 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 also 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 inhibitor.

MONITOR: Coadministration with encorafenib may increase the plasma concentrations of drugs that are substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT2), organic anion transporter (OAT1, OAT3), organic anion transporting polypeptide (OATP1B1, OATP1B3), or uridine diphosphate glucuronosyltransferase (UGT) 1A1. In in vivo studies, encorafenib has been shown to be an inhibitor of OATP1B1, 1B3, and BCRP. In vitro studies have demonstrated it to be an inhibitor of OCT2, OAT1, OAT3, and P-gp at expected clinical concentrations as well as a potent, reversible inhibitor of UGT1A1. Administration of a single dose of rosuvastatin, an OATP1B1, OATP1B3 and BCRP substrate, after repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily, resulted in increased systemic exposure (AUC) and peak plasma concentration (Cmax) of rosuvastatin by approximately 1.6 fold and 2.7 fold respectively.

MANAGEMENT: Caution is advised if encorafenib must be used concomitantly with drugs that are substrates of the affected transporters or UGT1A1, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever encorafenib is added to or withdrawn from therapy.