Drug Interactions between encorafenib and Meprozine

ADJUST DOSE: The central nervous system and respiratory depressant effects of meperidine may be potentiated by concomitant use of other agents with CNS depressant effects. An increased risk of serious adverse reactions such as respiratory depression, hypotension, profound sedation, syncope, coma, and even death should be considered, particularly in elderly or debilitated patients.

MANAGEMENT: Caution and dosage adjustments are advisable when meperidine is used in combination with other narcotic analgesics, general anesthetics, phenothiazines, sedative-hypnotics, tranquilizers, tricyclic antidepressants, or other CNS depressants such as alcohol. A lower dosage of meperidine should be considered initially, then titrated carefully according to pain level and clinical response. Meperidine dosage reductions of 25% to 50% have been recommended for patients receiving phenothiazines and other tranquilizers. Patients should be advised to avoid rising abruptly from a sitting or recumbent position, and to notify their physician if they experience dizziness, lightheadedness, orthostasis, syncope, tachycardia, or excessive CNS effects that interfere with their normal activities. Patients should also avoid driving or operating hazardous machinery until they know how these medications affect them.

GENERALLY AVOID: Coadministration with encorafenib may significantly reduce the plasma concentrations and effects of drugs that are primarily metabolized by CYP450 3A4, which may lead to decreased efficacy of the concomitant drug(s). Encorafenib is a potent CYP450 3A4 inducer in vivo. 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.

MANAGEMENT: Concomitant use of encorafenib and sensitive CYP450 3A4 substrates or substrates with narrow therapeutic ranges should generally be avoided. These drugs include, but are not limited to: alfentanil, cisapride, colchicine, cyclosporine, fentanyl, ivacaftor, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, quinidine, sildenafil, ergot derivatives, macrolide immunosuppressants, and vinca alkaloids. The prescribing information for the concomitant medication may be consulted to assess the benefits versus risks of coadministration, as well as any dosage adjustments that may be required during coadministration and/or following the discontinuation of a potent CYP450 3A4 inducer.

GENERALLY AVOID: Encorafenib may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. A dedicated study to evaluate the QT prolongation potential of encorafenib has not been conducted. Based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean QTcF change from baseline was 18 msec following administration of the recommended dose of encorafenib in combination with binimetinib. In the COLUMBUS trial, an increase in QTcF to >500 msec was measured in 0.5% (1/192) of patients who received encorafenib with binimetinib. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of encorafenib with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Hypokalemia and hypomagnesemia should be corrected prior to initiation of encorafenib treatment, and electrolytes periodically monitored during treatment. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Withhold, reduce dose, or permanently discontinue encorafenib in accordance with the product labeling for QTc exceeding 500 msec.