Drug Interactions between pilocarpine and ponesimod

GENERALLY AVOID: The risk of severe bradycardia and atrioventricular (AV) block may be increased during initiation of ponesimod 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. Posenimod can cause a transient decrease in heart rate during initiation of therapy that is usually apparent within an hour of the first dose and reaches its nadir within 2 to 4 hours. The heart rate typically recovers to baseline levels 4 to 5 hours after administration, and the effect diminishes with repeated dosing on subsequent days, indicating tolerance. In an active-controlled clinical study, bradycardia at treatment initiation and sinus bradycardia on ECG (defined as heart rate less than 50 bpm) occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving teriflunomide. The mean decrease in heart rate on day 1 of ponesimod dosing was 6 bpm. Following day 1, decreases in heart rate were less pronounced. Post-dose heart rates below or equal to 40 bpm were rarely observed. However, decreases in heart rate induced by ponesimod can be reversed by atropine if necessary. In a drug-drug interaction and pharmacodynamics safety study, an additive negative chronotropic effect on heart rate was observed when the dose titration regimen of ponesimod was administered to subjects receiving propranol 80 mg once daily at steady state. Compared to ponesimod alone, the combination of propranolol and the first dose of ponesimod (2 mg) resulted in a mean hourly heart rate decrease of 12.4 bpm (90% CI: -15.6 to -9.1). Compared to ponesimod alone, propranolol administered in combination with the first maintenance dose of ponesimod (20 mg) resulted in a 7.4 bpm (90% CI: -10.9 to -3.9) mean hourly heart rate decrease. No significant changes in pharmacokinetics of ponesimod or propranolol were observed.

MANAGEMENT: Experience with ponesimod is limited in patients receiving concomitant therapy with drugs that decrease heart rate. For patients receiving a stable dose of a beta-blocker, resting heart rate should be considered before introducing ponesimod treatment. If resting heart rate is greater than 55 bpm with chronic beta-blocker treatment, ponesimod can be introduced. If resting heart rate is 55 bpm or less, beta-blocker treatment should be interrupted until baseline heart rate is greater than 55 bpm. Then, ponesimod can be initiated and beta-blocker treatment can be reinitiated after ponesimod has been up-titrated to the target maintenance dosage. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. For patients taking other drugs that decrease heart rate, treatment with ponesimod should generally not be initiated without consultation from a cardiologist to determine the most appropriate monitoring.

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