Fingolimod

Dosage and Administration ( 2.1 ) 6/2024 Warnings and Precautions ( 5.3 , 5.9 ) 8/2023 Warnings and Precautions ( 5.3 , 5.4 , 5.12 ) 6/2024

1 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 capsules are 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 )

2 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 …

3 DOSAGE FORMS AND STRENGTHS Fingolimod capsules are available as: • 0.5 mg, size 3 hard gelatin capsules with a light yellow to yellow opaque cap and off-white to white opaque body, imprinted with a Glenmark Logo 'G' on the cap and '559' on the capsule body in black ink containing white to off-white powder. 0.5 mg hard capsules ( 3 )

4 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 )

6 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 …

7 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 capsules treatment. ( 5.2 , 7.3 ) 7.1 QT Prolonging Drugs Fingolimod capsules have 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 capsules 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 capsules and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. 7.3 Vaccines Fingolimod capsules reduce the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with fingolimod capsules [see Clinical Pharmacology ( 12.2 )] . Avoid the use of live attenuated vaccines during and for 2 months after treatment with fingolimod capsules 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 capsules. 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 capsules [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 capsules 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 capsules treatment may result in an additional decrease in heart rate, concomitant use of these drugs during fingolimod capsules 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 capsules. 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 capsules reduce 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 capsules. A recent CBC should be available before initiating treatment with fingolimod capsules.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available observational pregnancy registry data suggest that use of Fingolimod Capsules are associated with an increased prevalenceof major birth defects in comparison to the general population. However, limitations in the number of exposed pregnant women and inthe study design preclude definitive conclusions (see Data). Data from prospective reports to the pregnancy registry are currently notsufficient to allow for an adequate assessment of the drug-associated risk for miscarriage. Based on findings from animal studies, Fingolimod Capsules 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/m2) 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, Fingolimod Capsules 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 Fingolimod Capsules because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping Fingolimod Capsules, patients had stopped Fingolimod Capsules because of pregnancy or planned pregnancy [ see Warnings and Precautions (5.9) ] . Data Human Data In a prospective observational GILENYA pregnancy registry (GPR) (2011 to 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 trimesterwas 8.2% (95% CI: 4.3 to 13.8) using the European Registration of Congenital Anomalies and Twin classification and 10.9% (95%CI: 6.4 to 17.1) using the Metropolitan Atlanta Congenital Defects Program classification. The most frequent major birth defects werecongenital heart defects, renal/urinary malformations, and limb/musculoskeletal malformations. Study limitations include no adjustmentfor 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 Fingolimod Capsules is similar to that observed in the general population. There is noevidence of clustering of specific birth defects with Fingolimod Capsules. 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/m2 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/m2 basis. When f …

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 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.

11 DESCRIPTION Fingolimod is a sphingosine 1-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 g/mol. Fingolimod capsules are 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 fingolimod capsule 0.5 mg is supplied as an imprinted hard-shell capsule containing the following inactive ingredients: dibasic calcium phosphate, magnesium stearate and empty hard gelatin capsules. The hard gelatin capsules contain gelatin, titanium dioxide, yellow iron oxide, black imprinting ink and yellow ink. The imprinting ink contains propylene glycol, and shellac, and additionally the black ink contains black iron oxide, and potassium hydroxide, and the yellow ink contains yellow iron oxide. fingolimod-hcl-structure.

10 OVERDOSAGE Fingolimod capsules can induce bradycardia as well as AV conduction blocks (including complete AV block). The decline in heart rate usually starts within 1 hour of the first dose and is maximal within 6 hours in most patients [see Warnings and Precautions ( 5.1 )]. In case of fingolimod capsules overdosage, observe patients overnight with continuous ECG monitoring in a medical facility, and obtain regular measurements of blood pressure [see Dosage and Administration ( 2.4 )]. Neither dialysis nor plasma exchange results in removal of fingolimod from the body.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 0.5 mg fingolimod capsules are hard gelatin capsules with a white or off-white opaque body and cap imprinted with “S2” on the cap with black ink. Fingolimod capsules are supplied as follows: Bottle of 30 capsules NDC 64980-449-03 Carton of 28 capsules containing 4 blister cards of 7 capsules per blister card NDC 64980-449-28 Carton of 7 capsules containing 1 blister card of 7 capsules per blister card NDC 64980-449-07 16.2 Storage and Handling Fingolimod capsules should be stored at 25oC (77oF); excursions permitted to 15o to 30oC (59o to 86oF) [See USP Controlled Room Temperature]. Protect from moisture.

16.1 How Supplied 0.5 mg fingolimod capsules are hard gelatin capsules with a white or off-white opaque body and cap imprinted with “S2” on the cap with black ink. Fingolimod capsules are supplied as follows: Bottle of 30 capsules NDC 64980-449-03 Carton of 28 capsules containing 4 blister cards of 7 capsules per blister card NDC 64980-449-28 Carton of 7 capsules containing 1 blister card of 7 capsules per blister card NDC 64980-449-07