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 fingolimod in the terminal phase, yielding 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 feces with amounts of each representing less than 2.5% of the dose.
Special Populations
Renal Impairment
In patients with severe renal impairment, fingolimod Cmax and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate Cmax and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the GILENYA 0.5 mg dose is appropriate for use in patients with renal impairment. The systemic exposure of two metabolites (M2 and M3) is increased by 3- and 13-fold, respectively. The toxicity of these metabolites has not been fully characterized.
A study in patients with mild or moderate renal impairment has not been conducted.
Hepatic Impairment
In subjects with mild, moderate, or severe hepatic impairment, no change in fingolimod Cmax was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment, fingolimod-phosphate Cmax was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-phosphate were not eva luated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment.
Patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions is greater [See Warnings and Precautions (5.5)].
No dose adjustment is needed in patients with mild or moderate hepatic impairment.
Race
The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of non-white patients in the clinical program.
Gender
Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics.
Geriatric patients
The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited.
Pharmacokinetic interactions
Ketoconazole
The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the ri |
