e majority of elevations occurred within 3-4 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of Gilenya. In a small number of patients (N=10 on 1.25 mg, N=2 on 0.5 mg) who experienced liver transaminase elevations 5x ULN and who continued on Gilenya therapy, the elevations returned to normal within approximately 5 months (see also section 4.4, Liver function).
Nervous system disorders
Rare events involving the nervous system which occurred in patients treated with fingolimod at higher doses (1.25 or 5.0 mg) include ischaemic and haemorrhagic strokes and posterior reversible encephalopathy syndrome. Neurological atypical disorders have also been reported, such as acute disseminated encephalomyelitis (ADEM)-like events.
Vascular disorders
Rare cases of peripheral arterial occlusive disease occurred in patients treated with fingolimod at higher doses (1.25 mg).
Respiratory system
Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining stable thereafter. At Month 24, the reduction from baseline values in percentage of predicted FEV1 was 3.1% for fingolimod 0.5 mg and 2.0% for placebo, a difference that resolved after treatment discontinuation. For DLCO the reductions at Month 24 were 3.8% for fingolimod 0.5 mg and 2.7% for placebo.
Lymphomas
Three cases of lymphoma, including one fatal case of Epstein-Barr virus (EBV) positive B-cell lymphoma, have been reported in a population of more than 4,000 patients (approximately 10,000 patient years) exposed to fingolimod during the clinical programme in multiple sclerosis at, or above, the recommended dose of 0.5 mg. This incidence of 3 in 10,000 patient years (95% CI: 0.6-8.8 per 10,000 patient years) compares to a background incidence of 1.9 in 10,000 patient years in the general population.
4.9 Overdose
No cases of overdose have been reported. However, single doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity.
Fingolimod can induce bradycardia and can slow atrioventricular conduction.
Neither dialysis nor plasma exchange results in removal of fingolimod from the body.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA27
Mechanism of action
Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolised by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, and readily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the central nervous system. By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes. This redistribution reduces the infiltration of pathogenic lymphocyte cells into the central nervous system, where they would be involved in nerve inflammation and nervous tissue damage. Animal stud
