Initiation of GILENYA treatment results in a decrease in heart rate [see Clinical Pharmacology (12.2)]. Observe all patients for a period of 6 hours for signs and symptoms of bradycardia. Should post-dose bradyarrhythmia-related symptoms occur, initiate appropriate management and continue observation until the symptoms have resolved.

To identify underlying risk factors for bradycardia and atrioventricular (AV) block, if a recent electrocardiogram (i.e. within 6 months) is not available, obtain one in patients using anti-arrhythmics including beta-blockers and calcium channel blockers, those with cardiac risk factors, as described below, and those who on examination have a slow or irregular heart beat prior to starting GILENYA.

Experience with GILENYA in patients receiving concurrent therapy with beta blockers or in those with a history of syncope is limited. GILENYA has not been studied in patients with sitting heart rate less than 55 bpm. GILENYA has not been studied in patients with second degree or higher AV block, sicksinussyndrome, prolonged QT interval, ischemic cardiac disease, or congestive heart failure. GILENYA has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Class Ia and Class III antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.

After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 decline is maximal at approximately 6 hours. Following the second dose a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within one month of chronic treatment. The mean decrease in heart rate in patients on GILENYA 0.5 mg at 6 hours after the first dose was approximately 13 beats per minute (bpm). Heart rates below 40 bpm were rarely observed. Adverse reactions of bradycardia following the first dose were reported in 0.5% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced mild to moderate dizziness, fatigue, palpitations, and chest pain that resolved within the first 24 hours on treatment.

Atrioventricular blocks

Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of firstdegree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Seconddegree AV blocks following the first dose were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5mg and N=347 on placebo), seconddegree AV blocks, usually Mobitz type I (Wenckebach) were reported in 3.7% (N=13) of patients receiving GILENYA 0.5 mg and 2% (N=7) of patients on placebo. The conduction abnormalities were usually transient andasymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. One patient developed syncope and complete AV bl