8.3 Nursing Mothers
Fingolimod is excreted in the milk of treated rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GILENYA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use
The safety and effectiveness of GILENYA in pediatric patients with MS below the age of 18 have not been established.

8.5 Geriatric Use
Clinical MS studies of GILENYA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. GILENYA should be used with caution in patients aged 65 years and over, reflecting the greater frequency of decreased hepatic, or renal, function and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment
Because fingolimod, but not fingolimod-phosphate, exposure is doubled in patients with severe hepatic impairment,patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions may be greater[See Warnings and Precautions (5.5)and Clinical Pharmacology (12.3)].

No dose adjustment is needed in patients with mild or moderate hepatic impairment.

8.7 Renal Impairment
The blood level of some GILENYA metabolites is increased (up to 13-fold) in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. The toxicity of these metabolites has not been fully explored. The blood level of these metabolites has not been assessed in patients with mild or moderate renal impairment.

10 OVERDOSAGE
No cases of overdosage have been reported. However, single doses up to 80-fold the recommended dose (0.5mg) resulted in no clinically significant adverse reactions. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity.

Neither dialysis nor plasma exchange results in removal of fingolimod from the body.

11 DESCRIPTION
Fingolimod is a sphingosine1-phosphate receptor modulator.

Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride. Its structure is shown below:

Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93.

GILENYA is provided as 0.5 mg hard gelatin capsules for oral use. Each capsule contains 0.56 mg of fingolimod hydrochloride, equivalent to 0.5 mg of fingolimod.

Each GILENYA 0.5 mg capsule contains the following inactive ingredients: gelatin, magnesium stearate, mannitol, titanium dioxide, yellow iron oxide.

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lympho