Drug Interaction Report

GENERALLY AVOID: The risk of severe bradycardia and atrioventricular (AV) block may be increased during initiation of siponimod treatment in patients receiving other drugs that slow heart rate or AV conduction such as beta-blockers, certain calcium channel blockers (e.g., diltiazem, verapamil), and digitalis. Siponimod can cause a decrease in heart rate during initiation of therapy that is apparent within an hour of the first dose, and the day 1 decline is maximal at approximately 3 to 4 hours. The maximal decrease in heart rate from baseline was seen between day 5 and 6. After day 6, heart rate starts increasing and reaches placebo levels within 10 days after treatment initiation. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, with a decrease of 5 to 6 bpm. Following day 1, decreases in heart rate are less pronounced. Heart rates below 40 bpm were rarely observed. In controlled clinical trials, bradycardia (including bradycardia, sinus bradycardia, and decreased heart rate) occurred in 6% of siponimod-treated patients compared to 3% of patients receiving placebo. Initiation of siponimod treatment has also resulted in transient AV conduction delays. First-degree AV block (prolonged PR interval on ECG) occurred in 5.1% of siponimod-treated patients and 1.9% of patients receiving placebo. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of siponimod initiation in less than 1.7% of patients. Bradycardia and conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours, but they occasionally required treatment with atropine. In a dedicated pharmacodynamics/safety study, the addition of propranolol to siponimod at steady-state resulted in less pronounced negative chronotropic effects than the addition of siponimod to propranolol at steady-state.

MANAGEMENT: Siponimod has not been adequately studied in patients receiving concomitant therapy with drugs that decrease heart rate. Treatment with siponimod should generally not be initiated in patients who are concurrently treated with heart rate-lowering drugs. Advice from a cardiologist should be sought if coadministration of siponimod and drugs that slow heart rate or AV conduction is considered. For patients receiving a stable dose of a beta-blocker, resting heart rate should be considered before introducing siponimod treatment. If resting heart rate is greater than 50 bpm with chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until baseline heart rate is greater than 50 bpm. Then, siponimod can be initiated and beta-blocker treatment can be reinitiated after siponimod has been up-titrated to the target maintenance dosage.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of alectinib and its major active metabolite, M4. According to the manufacturer, a high-fat, high-calorie meal increased the combined systemic exposure (AUC) of alectinib and M4 by 3.1-fold following oral administration of a single 600 mg dose of alectinib.

MANAGEMENT: To ensure maximal oral absorption, alectinib should be administered with food.