Fingolimod

INDICATIONS AND USAGE Fingolimod capsules are 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. Fingolimod hydrochloride 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 )

DOSAGE AND ADMINISTRATION • Assessments are required prior to initiating fingolimod capsules. ( 2.1 ) • Recommended dosage for adults and pediatric patients (10 years of age and older) weighing more than 40 kg: 0.5 mg orally once daily, with or without food. ( 2.2 , 2.3 ) • Recommended dosage for pediatric patients (10 years of age and above) weighing less than or equal to 40 kg: 0.25 mg orally once daily, with or without food. ( 2.2 , 2.3 ) • First-Dose Monitoring (including reinitiation after discontinuation greater than 14 days and dose increases): o Observe all patients for bradycardia for at least 6 hours; monitor pulse and blood pressure hourly. Electrocardiograms (ECGs) prior to dosing and at end of observation period required. ( 2.4 ) o Monitor until resolution if heart rate < 45 beats per minute (bpm) in adults, < 55 bpm in patients aged 12 years and above, or < 60 bpm in pediatric patients aged 10 to below 12 years, atrioventricular (AV) block, or if lowest postdose heart rate is at the end of the observation period. ( 2.4 ) o Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. ( 2.4 ) o Observe patients overnight if at higher risk of symptomatic bradycardia, heart block, prolonged QTc interval, or if taking drugs with known risk of torsades de pointes. ( 2.4 , 7.1 ) 2.1 Assessment Prior to Initiating Fingolimod Capsules Cardiac Evaluation Obtain a cardiac evaluation in patients with certain preexisting conditions [see Warnings and Precautions ( 5.1 )] . Prior to starting treatment, determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.5 )] . Complete Blood Count (CBC) Review results of a recent CBC [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.6 )] . Serum Transaminases (ALT and AST) and Total Bilirubin Levels Prior to starting treatment with fingolimod capsules (i.e., within 6 months), obtain serum transaminases [alanine transaminase (ALT) and aspartate transferase (AST)] and total bilirubin levels [see Warnings and Precautions ( 5.5 )] . Ophthalmic Assessment Obtain a baseline evaluation of the fundus, including the macula, near the start of the treatment with fingolimod capsules [see Warnings and Precautions ( 5.4 )] . Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of fingolimod capsules. If a suspicious skin lesion is observed, it should be promptly evaluated [see Warnings and Precautions ( 5.12 )] . Prior Medications If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with fingolimod capsules [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.4 )] . Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating fingolimod capsules; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with fingolimod capsules [see Warnings and Precautions ( 5.2 )] . It is recommended that pediatric patients if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating fingolimod capsules therapy. 2.2 Important Administration Instructions Patients who initiate fingolimod capsules, and those who reinitiate treatment after discontinuation for longer than 14 days, require first-dose monitoring. This monitoring is also recommended when the dose is increased in pediatric patients [see Dosage and Administration ( 2.4 , 2.5 )] . Fingolimod capsules can be taken with or without food. 2.3 Recommended Dosage In adults and pediatric patients 10 years of age and older weighing more than 40 kg, the recommended dosage of fingolimod capsules is 0.5 mg orally once-daily. In pediatric patients 10 years of age and older weighing less than or equal to 40 kg, the recommended dosage of fingolimod capsules is 0.25 mg orally once daily. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. 2.4 First-Dose Monitoring Initiation of fingolimod capsules treatment results in a decrease in heart rate, for which monitoring is recommended [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 )] . Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients. First 6-Hour Monitoring Administer the first dose of fingolimod capsules in a setting in which resources to appropriately manage symptomatic bradycardia are available. Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Additional Monitoring After 6-Hour Monitoring Continue monitoring until the abnormality resolves if any of the following is present (even in the absence of symptoms) after 6 hours: • the heart rate 6 hours postdose is less than 45 beats per minute (bpm) in adults, less than 55 bpm in pediatric patients 12 years of age and older, or less than 60 bpm in pediatric patients 10 or 11 years of age; • the heart rate 6 hours postdose is at the lowest value postdose suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; • the ECG 6 hours postdose shows new onset second degree or higher atrioventricular (AV) block. If postdose symptomatic bradycardia occurs, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose. Overnight Monitoring Continuous overnight ECG monitoring in a medical facility should be instituted: • in patients that require pharmacologic intervention for symptomatic bradycardia. In these patients, the first-dose monitoring strategy should be repeated after the second dose of fingolimod capsules; • in patients with some preexisting heart and cerebrovascular conditions [see Warnings and Precautions ( 5.1 )] ; • in patients with a prolonged QTc interval before dosing or during 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )] ; • in patients receiving concurrent therapy with drugs that slow heart rate or AV conduction [see Drug Interactions ( 7.5 )] . 2.5 Monitoring After Reinitiation of Therapy Following Discontinuation When restarting fingolimod capsules after discontinuation for more than 14 days after the first month of treatment, perform first-dose monitoring, because effects on heart rate and AV conduction may recur on reintroduction of fingolimod capsules treatment [see Dosage and Administration ( 2.4 )] . The same precautions (first-dose monitoring) as for initial dosing are applicable. Within the first 2 weeks of treatment, first-dose procedures are recommended after interruption of 1 day or more; during Weeks 3 and 4 of treatment, first-dose procedures are recommended after treatment interruption of more than 7 days.

WARNINGS AND PRECAUTIONS • Infections: Fingolimod 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 fingolimod 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 fingolimod. 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 fingolimod 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 fingolimod. ( 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 fingolimod. ( 5.8 , 8.1 , 8.3 ) • Severe Increase in Disability After Stopping Fingolimod : 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 fingolimod treatment initiation [ see Dosage and Administration ( 2.4 ) ]. Reduction in Heart Rate After the first dose of fingolimod, 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 fingolimod capsules 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 fingolimod-induced bradycardia, or experience serious rhythm disturbances after the first dose of fingolimod. Prior to treatment with fingolimod, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and if treated with fingolimod, should be monitored overnight with continuous ECG in a medical facility after the first dose. Since initiation of fingolimod 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 fingolimod 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 fingolimod 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 fingolimod 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 fingolimod 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 fingolimod and 2% (N=7) of patients on placebo. Of the 14 patients receiving fingolimod, 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 fingolimod. 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 fingolimod is uncertain. Cases of syncope were also reported after the first dose of fingolimod capsules. 5.2 Infections Risk of Infections Fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. Fingolimod 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 fingolimod. Before initiating treatment with fingolimod, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with fingolimod 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 fingolimod to report symptoms of infections to a physician. Patients with act

CONTRAINDICATIONS Fingolimod capsules are 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 fingolimod capsules. 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 )

DRUG INTERACTIONS Systemic Ketoconazole: Monitor during concomitant use. ( 7.2 , 12.3 ) Vaccines: Avoid live attenuated vaccines during, and for 2 months after stopping fingolimod hydrochloride treatment. ( 5.2 , 7.3 ) 7.1 QT Prolonging Drugs Fingolimod hydrochloride 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 fingolimod hydrochloride 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 fingolimod hydrochloride and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. 7.3 Vaccines Fingolimod hydrochloride reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with fingolimod hydrochloride [ see Clinical Pharmacology (12.2) ]. Avoid the use of live attenuated vaccines during and for 2 months after treatment with fingolimod hydrochloride 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 fingolimod capsules 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 fingolimod hydrochloride. 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 fingolimod hydrochloride [ see Warnings and Precautions (5.2) ]. 7.5 Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) Experience with fingolimod hydrochloride 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 fingolimod hydrochloride treatment may result in an additional decrease in heart rate, concomitant use of these drugs during fingolimod hydrochloride 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 fingolimod hydrochloride. 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 fingolimod hydrochloride 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 fingolimod hydrochloride. A recent CBC should be available before initiating treatment with fingolimod hydrochloride.

ADVERSE REACTIONS 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 Fingolimod Capsules [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 Fingolimod Capsules 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 Solco Healthcare US, LLC at 1-866-257-2597 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 1,212 patients with relapsing forms of multiple sclerosis received fingolimod capsules 0.5 mg. This included 783 patients who received fingolimod capsules 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received fingolimod capsules 0.5 mg in the 1-year active-controlled trial (Study 2). The overall exposure in the controlled trials was equivalent to 1,716 person-years . Approximately 1,000 patients received at least 2 years of treatment with fingolimod capsules 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to fingolimod capsules 0.5 mg was approximately 4,119 person-years. In placebo-controlled trials, the most frequent adverse reactions (incidence ≥ 10% and greater than placebo) for fingolimod capsules 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 fingolimod capsules 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 fingolimod capsules-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 Fingolimod Capsules 0.5 mg at ≥ 1% Higher Rate Than for Placebo) Fingolimod Capsules 0.5 mg Placebo Adverse drug reactions N = 783 % 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 Abbreviations: ALT, alanine transaminase; AST, aspartate transferase; GGT, gamma-glutamyl transferase. 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 fingolimod capsules 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 fingolimod capsules doses (1.25 mg to 5 mg) higher than recommended for use in MS. Similar events have been reported with fingolimod capsules 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 fingolimod capsules 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 fingolimod capsules-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 fingolimod capsules, 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 fingolimod capsules 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 fingolimod capsules -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 fingolimod capsules. 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 )]

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 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.