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, 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 and asymptomatic, 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 block following the first dose of fingolimod 1.25 mg (a dose higher than recommended) in an uncontrolled study.

Re-initiation of therapy following discontinuation

If GILENYA therapy is discontinued for more than two weeks the effects on heart rate and AV conduction may recur on reintroduction of GILENYA treatment and the same precautions as for initial dosing should apply.

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. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to re-initiation of therapy. Because the elimination of fingolimod after discontinuation may take up to two months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved.

Two patients died of herpetic infections during GILENYA controlled studies in the premarketing database (one disseminated primary herpes zoster and one herpes simplex encephalitis). In both cases, the patients were receiving a fingolimod dose (1.25 mg) higher than recommended for the treatment of MS (0.5 mg), and had received high dose corticosteroid therapy for suspected MS relapse. No deaths due to viral infections occurred in patients treated with GILENYA 0.5 mg in the premarketing database.

In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients.

Concomitant use with antineoplastic, immunosuppressive or immune modulating therapies

GILENYA has not been administered concomitantly with antineoplastic, immunosuppressive or immune modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies would be expected to increase the risk of immunosuppression [see Drug Interactions (7)].

Varicella zoster virus antibody testing/