Drug Interactions between revumenib and vemurafenib

GENERALLY AVOID: Vemurafenib can cause concentration-dependent 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. The effect of vemurafenib 960 mg administered twice daily on QTc interval was evaluated in a multicenter, open-label, single-arm study consisting of 132 patients with BRAF V600E mutation-positive metastatic melanoma. No changes in mean QTc interval exceeding 20 ms from baseline were detected in the trial. In the first month of treatment, the largest mean increase from baseline was 12.8 ms, observed at 2 hours post-dose on Day 15. In the first 6 months of treatment, the largest mean increase from baseline was 15.1 ms, which was detected at a predose time point. 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, hypocalcemia). Moreover, 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 vemurafenib with other drugs that can prolong the QT interval is not recommended. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting vemurafenib therapy and after dose modification. An ECG should also be obtained 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter (or more often as clinically indicated). Vemurafenib should not be started in the presence of uncorrected electrolyte abnormalities or a baseline QTc greater than 500 ms. Likewise, treatment should be interrupted if QTc exceeds 500 ms. Any electrolyte abnormalities must then be corrected and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) under control prior to resuming treatment. Vemurafenib may be restarted once QTc decreases below 500 ms, but at a reduced dosage as described in the product labeling. Permanent discontinuation of treatment is recommended if, after correction of associated risk factors, both the QTc is greater than 500 ms and the QTc increase is greater than 60 ms from pretreatment values. 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.