Pulmonary function

Single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. In a14-day study of 0.5, 1.25, or 5 mg/day, fingolimodwas not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine.Subjects on fingolimod treatment had a normal bronchodilator response to inhaled beta-agonists.

In a 14-day placebo-controlled study of patients with moderate asthma, no effect was seen for GILENYA 0.5mg (recommended dose in MS). A10% reduction in mean FEV1 at 6 hour after dosing was observed in patients receiving fingolimod 1.25 mg (a dose higher than recommended for use in MS) on Day 10 of treatment. Fingolimod 1.25 mg was associated with a5-fold increase in the use of rescue short acting beta-agonists.

12.3 Pharmacokinetics
Absorption

The Tmaxof fingolimod is 12-16 hours. The apparent absolute oral bioavailabilityis 93%.

Food intake does not alter Cmax or exposure (AUC) of fingolimod or fingolimod-phosphate. Therefore GILENYA may be taken without regard to meals.

Steady-stateblood concentrations are reached within 1 to 2months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

Distribution

Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod-phosphate are >99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment.

Fingolimod is extensively distributed to body tissueswith a volume of distribution of about 1200±260 L.

Metabolism

The biotransformation of fingolimod in humans occurs by three main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate, 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 analogs of fingolimod.

Fingolimod is primarily metabolized via human CYP4F2 with a minor contribution of CYP2D6, 2E1, 3A4, and 4F12. Inhibitors or inducers of these isozymes might alter the exposure of fingolimod or fingolimod-phosphate. The involvement of multiple CYP isoenzymes in the oxidation of fingolimod suggests that the metabolism of fingolimod will not be subject to substantial inhibition in the presence of an inhibitor of a single specific CYP isozyme.

Following single oral administration of [14C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post-dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites [M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%), and M30 ceramide metabolite (7.3%)].

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-phosphate decline in parallel with those of fing