The European Medicines Agency has deferred the obligation to submit the results of studies with Gilenya in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

 Pharmacokinetic data were obtained in healthy volunteers, in renal transplant patients and in multiple sclerosis patients.

The pharmacologically active metabolite responsible for efficacy is fingolimod phosphate.

Absorption

Fingolimod absorption is slow (tmax of 12-16 hours) and extensive (85%). The apparent absolute oral bioavailability is 93% (95% confidence interval: 79-111%). Steady-state-blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

Food intake does not alter Cmax or exposure (AUC) of fingolimod. Fingolimod phosphate Cmax was slightly increased by 34% but AUC was unchanged. Therefore, Gilenya may be taken without regard to meals (see section 4.2).

Distribution

Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%. Fingolimod phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod phosphate are highly protein bound (>99%).

Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1,200±260 litres.

Biotransformation

Fingolimod is transformed in humans by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogues of fingolimod. The main enzyme involved in the metabolism of fingolimod is partially identified and may be either CYP4F2 or CYP3A4.

Following single oral administration of [14C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 34 days post dose of total radiolabelled components, are fingolimod itself (23%), fingolimod phosphate (10%), and inactive metabolites (M3 carboxylic acid metabolite (8%), M29 ceramide metabolite (9%) and M30 ceramide metabolite (7%)).

Elimination

Fingolimod blood clearance is 6.3±2.3 l/h, and the average apparent terminal half-life (t1/2) is 6-9 days. Blood levels of fingolimod and fingolimod phosphate decline in parallel in the terminal phase, leading to similar half-lives for both.

After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted intact in urine but are the major components in the faeces, with amounts representing less than 2.5% of the dose each. After 34 days, the recovery of the administered dose is 89%.

Linearity

Fingolimod and fingolimod phosphate concentrations increase in an apparently dose proportional manner after multiple once-daily doses of 0.5 mg or 1.25 mg.

Characteristics in specific groups of patients

The pharmacokinetics of fingol