Drug Interactions between Gilenya and Lexxel

MONITOR: The risk of bradycardia and atrioventricular (AV) block may be increased during initiation of fingolimod treatment in patients receiving beta-blockers, calcium channel blockers, digitalis, or other drugs that can slow the heart rate or AV conduction such as alectinib, atazanavir, flecainide, ivabradine, lacosamide, lithium, mefloquine, moricizine, propafenone, succinylcholine, thalidomide, H2-receptor antagonists, tricyclic antidepressants, and anticholinesterase or cholinergic agents. Fingolimod can cause a decrease in heart rate during initiation of therapy that is apparent within an hour of the first dose and maximal at approximately 6 hours postdose in most cases, but occasionally up to 20 hours after the first dose. Further, but smaller decreases in heart rate may occur after the second dose, although heart rate eventually returns to baseline within one month of chronic treatment. The mean decrease in heart rate in patients receiving fingolimod 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. In controlled clinical trials, adverse reactions of symptomatic bradycardia (hypotension, dizziness, fatigue, palpitations, chest pain) following the first dose were reported in 0.5% of patients receiving fingolimod 0.5 mg, compared to no patient on placebo. Initiation of fingolimod treatment has also resulted in transient AV conduction delays. First- and second-degree AV block (prolonged PR interval on ECG) following the first dose were each reported in 0.1% of patients receiving fingolimod 0.5 mg, compared to no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose, second degree AV blocks, usually Mobitz type I (Wenckebach), were reported in 3.7% of patients receiving fingolimod 0.5 mg and 2% of patients receiving placebo. Bradycardia and 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.

MANAGEMENT: Fingolimod has not been adequately studied in patients receiving other drugs that can slow the heart rate or AV conduction. Close monitoring is recommended during initiation of fingolimod treatment in these patients. The first dose should always be administered in a setting where resources to appropriately manage symptomatic bradycardia are available. Patients should be observed for a period of six hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. An electrocardiogram should be obtained prior to dosing and at the end of the observation period. Additional observation is recommended if the heart rate 6 hours postdose is less than 45 bpm or is at the lowest value postdose, or if the ECG 6 hours postdose shows new onset second-degree or higher AV block. Should postdose symptomatic bradycardia occur, initiate appropriate management, begin continuous ECG monitoring, and continue observation until the symptoms have resolved. Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first-dose monitoring strategy should be repeated after the second dose of fingolimod. The same precautions are applicable if, after the first month of treatment, fingolimod is discontinued for more than two weeks and then restarted, since the effects on heart rate and AV conduction may recur on reintroduction of fingolimod. Within the first 2 weeks of treatment, first-dose procedures are also recommended after interruption of one day or more; during week 3 and 4 of treatment, first-dose procedures are recommended after treatment interruption of more than 7 days.

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Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive hypotensive effects. While these drugs are often safely used together, careful monitoring of the systemic blood pressure is recommended during coadministration, especially during the first one to three weeks of therapy.

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