Drug Interactions between alectinib and etrasimod

MONITOR: The risk of transient bradycardia and atrioventricular (AV) block may be increased during initiation of etrasimod treatment in patients receiving other drugs that slow the heart rate or AV conduction such as beta-blockers, certain calcium channel blockers (e.g., diltiazem, verapamil), and digitalis. Etrasimod may cause a decrease in heart rate during initiation of therapy. In the randomized placebo-controlled studies in patients with ulcerative colitis UC-1 and UC-2, following an initial dose of 2 mg on day 1, the greatest mean decrease in heart rate from baseline was 7.2 bpm and occurred at hour 2 (UC-2) and hour 3 (UC-1). In studies UC-2 and UC-3, bradycardia was reported on day 1 in 2.9% of patients on etrasimod compared to none in the placebo group. On Day 2, bradycardia was reported in 1 patient (0.3%) treated with etrasimod compared to none in the placebo group. Overall, subjects who experienced bradycardia were generally asymptomatic. Few subjects experienced symptoms such as dizziness, and these symptoms resolved without intervention. Initiation of etrasimod treatment has also resulted in transient AV conduction delays. Initiation of etrasimod in patients stabilized on beta blockers did not cause additive heart rate reduction. However, the effects on heart rate reduction from initiating a beta blocker or other drugs that may decrease the heart rate in patients stabilized on etrasimod therapy are unknown.

MANAGEMENT: Advice from a cardiologist should be sought before initiation of beta blockers or drugs that may decrease heart rate (e.g., calcium channel blockers) in patients on a stable dose of etrasimod. According to the manufacturer, etrasimod can be initiated in patients stabilized on beta blockers. Some authorities advise that beta blocker therapy can also be initiated in patients who have been stabilized on etrasimod therapy for at least 7 consecutive days. However, prior to starting etrasimod, temporary interruption of the beta blocker therapy may be required, depending on the patient's resting heart rate. Some authorities advise monitoring for signs and symptoms of symptomatic bradycardia (e.g., hourly pulse and BP measurement and a pre- and post-dose ECG) for 4 hours after the first dose of etrasimod in patients with preexisting cardiac conditions such as a resting heart rate of less than 50 beats per minute, second-degree (Mobitz type I) AV block, or a history of myocardial infarction or heart failure. Cardiologist advice should also be sought if etrasimod is considered for use in patients with significant QT prolongation (QTcF greater than 450 msec in males or 470 msec in females), patients with arrhythmias requiring treatment with Class 1a or Class III antiarrhythmic agents, patients with unstable ischemic heart disease, heart failure, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension. The use of etrasimod in patients with a history of Mobitz type I second-degree AV block is considered contraindicated unless the patient has a functioning pacemaker. The manufacturer's product labeling and local treatment protocols should also be consulted for additional guidance.