ss Ia or Class III anti-arrhythmic drugs
5 WARNINGS AND PRECAUTIONS
5.1 Bradyarrhythmia and Atrioventricular Blocks
Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA treatment initiation [see Dosage and Administration (2)].
Reduction in heart rate
After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8-10 hours post dose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. Adverse reactions of symptomatic 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 hypotension, dizziness, fatigue, palpitations, and chest pain that usually resolved within the first 24 hours on treatment.
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.
Atrioventricular blocks
Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of first-degree 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. Second-degree 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 0.5 mg and N=347 on placebo), second-degree AV blocks, Mobitz types I (Wenckebach) and/or II, 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 and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol.
Post-marketing experience
In the post-marketing setting, third degree AV block and AV block with junctional escape have been observed during the first-dose six-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or pre-existing disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA.
5.2 Infections
Risk of infections
GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20 - 30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature [see Clinical Pharmacology (12.2)].
Before initiating treatment with GILENYA, a recent CBC (i.e. within 6 months) should be available |
