Fingolimod Hydrochloride

GILENYA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older. GILENYA is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older. ( 1 )

GILENYA is available as: 0.25 mg hard capsules with an ivory opaque body and cap, with black radial imprint “FTY 0.25 mg” on the cap and a black radial band on the capsule body. 0.5 mg hard capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and 2 radial bands imprinted on the capsule body with yellow ink. 0.25 mg hard capsules ( 3 ) 0.5 mg hard capsules ( 3 )

GILENYA is contraindicated in patients who have: in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure a history or presence of Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.1)] a baseline QTc interval ≥ 500 msec cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs had a hypersensitivity reaction to fingolimod or any of the excipients in GILENYA. Observed reactions include rash, urticaria and angioedema upon treatment initiation [see Warnings and Precautions (5.14)] . Recent myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure with hospitalization, or Class III/IV heart failure. ( 4 ) History of Mobitz Type II 2 nd degree or 3 rd degree AV block or sick sinus syndrome, unless patient has a pacemaker. ( 4 ) Baseline QTc interval ≥ 500 msec. ( 4 ) Cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs. ( 4 ) Hypersensitivity to fingolimod or its excipients. ( 4 )

Infections: GILENYA may increase the risk. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment and for 2 months after discontinuation. Do not start in patients with active infections. ( 5.2 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold GILENYA at the first sign or symptom suggestive of PML. ( 5.3 ) Macular Edema: Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with GILENYA. Conduct an evaluation of the fundus, including the macula, 3 to 4 months after treatment start, periodically while on therapy and any time there is a change in vision. Consider discontinuing GILENYA if macular edema develops. Diabetes mellitus and uveitis increase the risk. ( 5.4 ) Liver Injury: Obtain liver enzyme results before initiation and periodically during treatment. Closely monitor patients with severe hepatic impairment. Discontinue if there is evidence of liver injury without other cause. ( 5.5 , 8.6 , 12.3 ) Posterior Reversible Encephalopathy Syndrome (PRES): If suspected, discontinue GILENYA. ( 5.6 ) Respiratory Effects: Evaluate when clinically indicated. ( 5.7 ) Fetal Risk: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 2 months after stopping GILENYA. ( 5.8 , 8.1 , 8.3 ) Severe Increase in Disability After Stopping GILENYA: Monitor for development of severe increase in disability following discontinuation and begin appropriate treatment as needed. ( 5.9 ) Tumefactive MS: Consider when severe MS relapse occurs during treatment or after discontinuation. Obtain imaging and begin treatment as needed. ( 5.10 ) Increased Blood Pressure (BP): Monitor BP in adult and pediatric patients during treatment. ( 5.11 ) Malignancies: Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended. Suspicious skin lesions should be evaluated. ( 5.12 )

5.1 Bradyarrhythmia and Atrioventricular Blocks Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during GILENYA treatment initiation [see Dosage and Administration (2.4)] . Reduction in Heart Rate After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 bpm in adults, and below 50 bpm in pediatric patients occurred rarely. In controlled clinical trials in adult patients, adverse reactions of symptomatic bradycardia following the first dose were reported in 0.6% of patients receiving GILENYA 0.5 mg and in 0.1% of patients on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain that usually resolved within the first 24 hours on treatment. Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility after the first dose. Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (> 450 msec adult and pediatric males, > 470 msec adult females, or > 460 msec pediatric females) before dosing or during 6-hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility. Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. Clinical data indicate effects of GILENYA on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms. Atrioventricular Blocks Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials in adult patients, first-degree AV block after the first dose occurred in 4.7% of patients receiving GILENYA and 1.6% of patients on placebo. In a study of 697 patients with available 24-hour Holter monitoring data after their first dose (N = 351 receiving GILENYA and N = 346 on placebo), second-degree AV blocks (Mobitz Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N = 14) of patients receiving GILENYA and 2% (N = 7) of patients on placebo. Of the 14 patients receiving GILENYA, 7 patients had 2:1 AV block (5 patients within the first 6 hours postdose and 2 patients after 6 hours postdose). All second-degree AV blocks on placebo were Mobitz Type I and occurred after the first 12 hours postdose. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. Postmarketing Experience In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA.

5.2 Infections Risk of Infections GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature [see Clinical Pharmacology (12.2)] . Life-threatening and fatal infections have occurred in association with GILENYA. Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. […]

The following serious adverse reactions are described elsewhere in labeling: Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)] Macular Edema [see Warnings and Precautions (5.4)] Liver Injury [see Warnings and Precautions (5.5)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.6)] Respiratory Effects [see Warnings and Precautions (5.7)] Fetal Risk [see Warnings and Precautions (5.8)] Severe Increase in Disability After Stopping GILENYA [see Warnings and Precautions (5.9)] Tumefactive Multiple Sclerosis [see Warnings and Precautions (5.10)] Increased Blood Pressure [see Warnings and Precautions (5.11)] Malignancies [see Warnings and Precautions (5.12)] Immune System Effects Following GILENYA Discontinuation [see Warnings and Precautions (5.13)] Hypersensitivity Reactions [see Warnings and Precautions (5.14)] Most common adverse reactions (incidence ≥ 10% and greater than placebo): Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received GILENYA 0.5 mg. This included 783 patients who received GILENYA 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received GILENYA 0.5 mg in the 1-year active-controlled trial (Study 2). The overall exposure in the controlled trials was equivalent to 1716 person-years. Approximately 1000 patients received at least 2 years of treatment with GILENYA 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to GILENYA 0.5 mg was approximately 4119 person-years. In placebo-controlled trials, the most frequent adverse reactions (incidence ≥ 10% and greater than placebo) for GILENYA 0.5 mg were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking GILENYA 0.5 mg, were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo). Table 1 lists adverse reactions in clinical studies in adults that occurred in ≥ 1% of GILENYA-treated patients and ≥ 1% higher rate than for placebo. Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥ 1% of Patients and Reported for GILENYA 0.5 mg at ≥ 1% Higher Rate Than for Placebo) Abbreviations: ALT, alanine transaminase; AST, aspartate transferase; GGT, gamma-glutamyl transferase. Adverse drug reactions GILENYA 0.5 mg N = 783 % Placebo N = 773 % Infections Influenza 11 8 Sinusitis 11 8 Bronchitis 8 5 Herpes zoster 2 1 Tinea versicolor 2 < 1 Cardiac disorders Bradycardia 3 1 Nervous system disorders Headache 25 24 Migraine 6 4 Gastrointestinal disorders Nausea 13 12 Diarrhea 13 10 Abdominal pain 11 10 General disorders and administration-site conditions Asthenia 2 1 Musculoskeletal and connective tissue disorders Back pain 10 9 Pain in extremity 10 7 Skin and subcutaneous tissue disorders Alopecia 3 2 Actinic keratosis 2 1 Investigations Liver transaminase elevations (ALT/GGT/AST) 15 4 Blood triglycerides increased 3 1 Respiratory, thoracic, and mediastinal disorders Cough 12 11 Dyspnea 9 7 Eye disorders Vision blurred 4 2 Vascular disorders Hypertension 8 4 Blood and lymphatic system disorders Lymphopenia 7 < 1 Leukopenia 2 < 1 Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin papilloma 3 2 Basal cell carcinoma 2 1 Adverse reactions of seizure, dizziness, pneumonia, eczema, and pruritus were also reported in Studies 1 and 3, but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%). Adverse reactions with GILENYA 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3. Vascular Events Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25 mg to 5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA in the postmarketing setting although a causal relationship has not been established. Seizure Cases of seizures, including status epilepticus, have been reported with the use of GILENYA in clinical trials and in the postmarketing setting in adults [see Adverse Reactions (6.2)] . In adult clinical trials, the rate of seizures was 0.9% in GILENYA-treated patients and 0.3% in placebo-treated patients. It is unknown whether these events were related to the effects of multiple sclerosis alone, to GILENYA, or to a combination of both. Pediatric Patients 10 Years of Age and Older In the controlled pediatric trial (Study 4), the safety profile in pediatric patients receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. In the pediatric study, cases of seizures were reported in 5.6% of GILENYA-treated patients and 0.9% of interferon beta-1a-treated patients [see Use in Specific Populations (8.4)] .

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of GILENYA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Hemolytic anemia and thrombocytopenia Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.5)] Infections: Infections, including cryptococcal infections [see Warnings and Precautions (5.2)] , human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer [see Warnings and Precautions (5.2)] , progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)] Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia Nervous System Disorders: Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.6)] , seizures, including status epilepticus [see Adverse Reactions (6.1)] Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps): Melanoma, Merkel cell carcinoma, cutaneous T-cell lymphoma (including mycosis fungoides), Kaposi’s sarcoma, squamous cell carcinoma [see Warnings and Precautions (5.12)] Skin and Subcutaneous Tissue Disorders: Hypersensitivity [see Warnings and Precautions (5.14)]

Systemic Ketoconazole: Monitor during concomitant use. ( 7.2 , 12.3 ) Vaccines: Avoid live attenuated vaccines during, and for 2 months after stopping GILENYA treatment. ( 5.2 , 7.3 ) 7.1 QT Prolonging Drugs GILENYA has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients on QT-prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] .

7.2 Ketoconazole The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is increased.

7.3 Vaccines GILENYA reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA [see Clinical Pharmacology (12.2)] . Avoid the use of live attenuated vaccines during and for 2 months after treatment with GILENYA because of the risk of infection. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating GILENYA therapy.

7.4 Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with GILENYA. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating GILENYA [see Warnings and Precautions (5.2)] .

7.5 Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) Experience with GILENYA in patients receiving concurrent therapy with drugs that slow the heart rate or AV conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers, such as diltiazem or verapamil) is limited. Because initiation of GILENYA treatment may result in an additional decrease in heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. Seek advice from the physician prescribing these drugs regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating GILENYA. Patients who cannot switch should have overnight continuous ECG monitoring after the first dose [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] .

7.6 Laboratory Test Interaction Because GILENYA reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with GILENYA. A recent CBC should be available before initiating treatment with GILENYA.

8.1 Pregnancy Risk Summary Available observational pregnancy registry data suggest that use of GILENYA is associated with an increased prevalence of major birth defects in comparison to the general population. However, limitations in the number of exposed pregnant women and in the study design preclude definitive conclusions ( see Data ). Data from prospective reports to the pregnancy registry are currently not sufficient to allow for an adequate assessment of the drug-associated risk for miscarriage. Based on findings from animal studies, GILENYA may cause fetal harm when administered to a pregnant woman. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including an increase in malformations (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose of 0.5 mg/day on a body surface area (mg/m 2 ) basis. The most common fetal visceral malformations in rats were persistent truncus arteriosus and ventricular septal defect. The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis ( see Data ). Advise pregnant women of the potential risk to a fetus. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations In females planning to become pregnant, GILENYA should be stopped 2 months before planned conception. The possibility of severe increase in disability should be considered in women who discontinue or are considering discontinuation of GILENYA because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping GILENYA, patients had stopped GILENYA because of pregnancy or planned pregnancy [see Warnings and Precautions (5.9)] . Data Human Data In a prospective observational GILENYA pregnancy registry (GPR) (2011 – 2024), the rate of major birth defects among 147 live births, stillbirths, or terminations of pregnancy due to fetal anomalies from women who were administered fingolimod during the first trimester was 8.2% (95% CI: 4.3-13.8) using the European Registration of Congenital Anomalies and Twin classification and 10.9% (95% CI: 6.4-17.1) using the Metropolitan Atlanta Congenital Defects Program classification. The most frequent major birth defects were congenital heart defects, renal/urinary malformations, and limb/musculoskeletal malformations. Study limitations include no adjustment for confounders, no re-adjudication in case of spontaneous resolution, lack of an internal comparator cohort, and small sample size. In fingolimod prospective pharmacovigilance data, the most frequent major birth defect types were similar to those reported in the GPR. The pattern of malformations reported for GILENYA is similar to that observed in the general population. There is no evidence of clustering of specific birth defects with GILENYA. Animal Data When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryofetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the recommended human dose (RHD) on a mg/m 2 basis. Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryofetal mortality and fetal growth retardation at the mid and high doses. The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m 2 basis. When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m 2 basis.

8.2 Lactation Risk Summary There are no data on the presence of fingolimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Fingolimod is excreted in the milk of treated rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GILENYA and any potential adverse effects on the breastfed infant from GILENYA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Pregnancy Testing The pregnancy status of females of reproductive potential should be verified prior to starting treatment with GILENYA [see Use in Specific Populations (8.1)] . Contraception Before initiation of GILENYA treatment, females of reproductive potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with GILENYA [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)] . Since it takes approximately 2 months to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period [see Warnings and Precautions (5.8, 5.13)] .

8.4 Pediatric Use Safety and effectiveness of GILENYA for the treatment of relapsing forms of multiple sclerosis in pediatric patients 10 to less than 18 years of age were established in one randomized, double-blind clinical study in 215 patients (GILENYA n = 107; intramuscular interferon (IFN) beta-1a n = 108) [see Clinical Studies (14.2)] . In the controlled pediatric study, the safety profile in pediatric patients (10 to less than 18 years of age) receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. In the pediatric study, cases of seizures were reported in 5.6% of GILENYA-treated patients and 0.9% of interferon beta-1a-treated patients. It is recommended that pediatric patients, if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating GILENYA therapy. Safety and effectiveness of GILENYA in pediatric patients below the age of 10 years have not been established. Juvenile Animal Toxicity Data In a study in which fingolimod (0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, changes in bone mineral density and persistent neurobehavioral impairment (altered auditory startle) were observed at all doses. Delayed sexual maturation was noted in females at the highest dose tested and in males at all doses. The bone changes observed in fingolimod-treated juvenile rats are consistent with a reported role of S1P in the regulation of bone mineral homeostasis. When fingolimod (0.5 or 5 mg/kg/day) was orally administered to rats from the neonatal period through sexual maturity, a marked decrease in T-cell dependent antibody response was observed at both doses. This effect had not fully recovered by 6 to 8 weeks after the end of treatment. Overall, a no-effect dose for adverse developmental effects in juvenile animals was not identified.

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. […]

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 sphingosine 1-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 lymphocyte migration into the central nervous system.