Macular oedema incidence is increased in multiple sclerosis patients with a history of uveitis (17% with a history of uveitis vs. 0.6% without a history of uveitis). Gilenya has not been studied in multiple sclerosis patients with diabetes mellitus, a disease which is associated with an increased risk for macular oedema (see section 4.4). In renal transplant clinical studies in which patients with diabetes mellitus were included, therapy with fingolimod 2.5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular oedema.

Bradyarrhythmia

Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays (see sections 4.4 and 5.1). In multiple sclerosis clinical studies the maximal decline in heart rate was seen 4-5 hours after treatment initiation, with declines in mean heart rate of 8 beats per minute for Gilenya 0.5 mg. Heart rate below 40 beats per minute was rarely observed in patients on Gilenya 0.5 mg. Heart rate returned to baseline within 1 month of chronic treatment. Bradycardia was generally asymptomatic but some patients experienced mild to moderate symptoms, including dizziness, fatigue and/or palpitations, which resolved within the first 24 hours after treatment initiation.

In multiple sclerosis clinical studies first-degree atrioventricular block (prolonged PR interval on electrocardiogram) was detected after treatment initiation in 4.7% of patients on fingolimod 0.5 mg, in 2.8% of patients on intramuscular interferon beta-1a, and in 1.5% of patients on placebo. Second-degree atrioventricular block was detected in less than 0.5% patients on Gilenya 0.5 mg. One case of transient third-degree atrioventricular block occurred three hours after the first dose of fingolimod 1.25 mg was administered and lasted for 30 seconds. The patient recovered spontaneously. The conduction abnormalities were typically transient, asymptomatic and resolved within the first 24 hours after treatment initiation. Although most patients did not require medical intervention, one patient on Gilenya 0.5 mg received isoprenaline for asymptomatic second-degree Mobitz I atrioventricular block.

Blood pressure

In multiple sclerosis clinical studies Gilenya 0.5 mg was associated with an average increase of approximately 2 mmHg in systolic pressure and approximately 1 mmHg in diastoic pressure, manifesting approximately 2 months after treatment initiation. This increase persisted with continued treatment. Hypertension was reported in 6.1% of patients on fingolimod 0.5 mg and in 3.8% of patients on placebo (see also section 4.4, Blood pressure effects).

Liver transaminases

In multiple sclerosis clinical studies 8% and 2% of patients treated with Gilenya 0.5 mg experienced asymptomatic elevation in serum levels of hepatic transaminases 3x ULN (upper limit of normal) and 5x ULN, respectively. Recurrence of liver transaminase elevations has occurred upon re-challenge in some patients, supporting a relationship to the medicinal product. Th