5 WARNINGS AND PRECAUTIONS

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 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.

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 active acute or chronic infections should not start treatment until the infection(s) is resolved.

In MS placebo-controlled trials in adult patients, the overall rate of infections (72%) with fingolimod was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in fingolimod- treated patients. Serious infections occurred at a rate of 2.3% in the fingolimod group versus 1.6% in the placebo group.

In the postmarketing setting, serious infections with opportunistic pathogens including viruses (e.g., John Cunningham virus [JCV], herpes simplex viruses 1 and 2, varicella zoster virus), fungi (e.g., cryptococci), and bacteria (e.g., atypical mycobacteria) have been reported with fingolimod. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and appropriate treatment.

Herpes Viral Infections

In placebo-controlled trials in adult patients, the rate of herpetic infections was 9% in patients receiving fingolimod 0.5 mg and 7% on placebo.

Two patients died of herpetic infections during controlled trials. One death was due to disseminated primary herpes zoster and the other was to herpes simplex encephalitis. In both cases, the patients were taking a 1.25 mg dose of fingolimod (higher than the recommended 0.5 mg dose) and had received high- dose corticosteroid therapy to treat suspected MS relapses.

Serious, life-threatening events of disseminated varicella zoster and herpes simplex infections, including cases of encephalitis and multiorgan failure, have occurred with fingolimod in the postmarketing setting. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving fingolimod and present with an atypical MS relapse or multiorgan failure.

Cases of Kaposi’s sarcoma have been reported in the postmarketing setting. Kaposi’s sarcoma is an angioproliferative disorder that is associated with infection with human herpes virus 8 (HHV-8). Patients with symptoms or signs consistent with Kaposi’s sarcoma should be referred for prompt diagnostic evaluation and management.

Cryptococcal Infections

Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, have been reported with fingolimod in the postmarketing setting. Cryptococcal infections have generally occurred after approximately 2 years of fingolimod treatment, but may occur earlier. The relationship between the risk of cryptococcal infection and the duration of treatment is unknown. Patients with symptoms and signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment.

Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies

In clinical studies, patients who received fingolimod did not receive concomitant treatment with antineoplastic, non- corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of fingolimod with any of these therapies, and also with corticosteroids, would be expected to increase the risk of immunosuppression [see Drug Interactions (7.4)].

When switching to fingolimod from immune-modulating or immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.

Varicella Zoster Virus Antibody Testing/Vaccination

Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating fingolimod. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with fingolimod, following which initiation of treatment with fingolimod should be postponed for 1 month to allow the full effect of vaccination to occur [see Drug Interactions (7.3), Use in Specific Populations (8.4)].

Human Papilloma Virus Infection

Human papilloma virus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported in patients treated with fingolimod in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation with fingolimod, taking into account vaccination recommendations. Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.

5.3 Progressive Multifocal Leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS who received fingolimod in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, were not taking any other immunosuppressive or immunomodulatory medications concomitantly, and did not have any ongoing systemic medical conditions resulting in compromised immune system function. The majority of cases have occurred in patients treated with fingolimod for at least 2 years. The relationship between the risk of PML and the duration of treatment is unknown.

At the first sign or symptom suggestive of PML, withhold fingolimod and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

Magnetic reasonace imaging (MRI) findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including fingolimod. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

If PML is confirmed, treatment with fingolimod should be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including fingolimod, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

5.4 Macular Edema

Fingolimod increases the risk of macular edema. Perform an examination of the fundus, including the macula in all patients before starting treatment, again 3 to 4 months after starting treatment, and again at any time after a patient reports visual disturbances while on fingolimod therapy.

A dose-dependent increase in the risk of macular edema occurred in the fingolimod clinical development program.

In 2-year double-blind, placebo-controlled studies in adult patients with multiple sclerosis, macular edema with or without visual symptoms occurred in 1.5% of patients (11/799) treated with fingolimod 1.25 mg, 0.5% of patients (4/783) treated with fingolimod 0.5 mg, and 0.4% of patients (3/773) treated with placebo. Macular edema occurred predominantly during the first 3 to 4 months of therapy. These clinical trials excluded patients with diabetes mellitus, a known risk factor for macular edema (see below Macular Edema in Patients with History of Uveitis or Diabetes Mellitus). Symptoms of macular edema included blurred vision and decreased visual acuity. Routine ophthalmological examination detected macular edema in some patients with no visual symptoms. Macular edema generally partially or completely resolved with or without treatment after drug discontinuation. Some patients had residual visual acuity loss even after resolution of macular edema. Macular edema has also been reported in patients taking fingolimod in the postmarketing setting, usually within the first 6 months of treatment.

Continuation of fingolimod in patients who develop macular edema has not been evaluated. A decision on whether or not to discontinue fingolimod therapy should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.

Macular Edema in Patients with History of Uveitis or Diabetes Mellitus

Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during fingolimod therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the combined clinical trial experience in adult patients with all doses of fingolimod, the rate of macular edema was approximately 20% in MS patients with a history of uveitis versus 0.6% in those without a history of uveitis. Fingolimod has not been tested in MS patients with diabetes mellitus. In addition to the examination of the fundus, including the macula prior to treatment and at 3 to 4 months after starting treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.

5.5 Liver Injury

Clinically significant liver injury has occurred in patients treated with fingolimod in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose and have also been reported after prolonged use. Cases of acute liver failure requiring liver transplant have been reported.

In 2-year placebo-controlled clinical trials in adult patients, elevation of liver enzymes (ALT, AST, and GGT) to 3-fold the upper limit of normal (ULN) or greater occurred in 14% of patients treated with fingolimod 0.5 mg and 3% of patients on placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on fingolimod and 1% of patients on placebo. The majority of elevations occurred within 6 to 9 months. In clinical trials, fingolimod was discontinued if the elevation exceeded 5 times the ULN. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

Prior to starting treatment with fingolimod (within 6 months), obtain serum transaminases (ALT and AST) and total bilirubin levels. Obtain transaminase levels and total bilirubin levels periodically until two months after fingolimod discontinuation.

Patients should be monitored for signs and symptoms of any hepatic injury. Measure liver transaminase and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. In this clinical context, if the patient is found to have an alanine aminotransferase (ALT) greater than three times the reference range with serum total bilirubin greater than two times the reference range, treatment with fingolimod should be interrupted. Treatment should not be resumed if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury.

Because fingolimod exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.6 Posterior Reversible Encephalopathy Syndrome

There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in adult patients receiving fingolimod. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, fingolimod should be discontinued.

5.7 Respiratory Effects

Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with fingolimod as early as 1 month after treatment initiation. In 2- year placebo-controlled trials in adult patients, the reduction from baseline in the percent of predicted values for FEV1 at the time of last assessment on drug was 2.8% for fingolimod 0.5 mg and 1% for placebo. For DLCO, the reduction from baseline in percent of predicted values at the time of last assessment on drug was 3.3% for fingolimod 0.5 mg and 0.5% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS placebo-controlled trials in adult patients, dyspnea was reported in 9% of patients receiving fingolimod 0.5 mg and 7% of patients receiving placebo. Several patients discontinued fingolimod because of unexplained dyspnea during the extension (uncontrolled) studies. Fingolimod has not been tested in MS patients with compromised respiratory function.

Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with fingolimod if clinically indicated.

5.8 Fetal Risk

Based on findings from animal studies, fingolimod may cause fetal harm when administered to a pregnant woman. In animal reproduction studies conducted in rats and rabbits, developmental toxicity was observed with administration of fingolimod at doses less than the recommended human dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate fingolimod from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping fingolimod treatment [see Use in Specific Populations (8.1, 8.3)].

5.9 Severe Increase in Disability After Stopping Fingolimod

Severe increase in disability accompanied by multiple new lesions on MRI has been reported after discontinuation of fingolimod in the postmarketing setting. Patients in most of these reported cases did not return to the functional status they had before stopping fingolimod. The increase in disability generally occurred within 12 weeks after stopping fingolimod, but was reported up to 24 weeks after fingolimod discontinuation.

Monitor patients for development of severe increase in disability following discontinuation of fingolimod and begin appropriate treatment as needed.

After stopping fingolimod in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) [see Warnings and Precautions (5.3)].

5.10 Tumefactive Multiple Sclerosis

MS relapses with tumefactive demyelinating lesions on imaging have been observed during fingolimod therapy and after fingolimod discontinuation in the postmarketing setting. Most reported cases of tumefactive MS in patients receiving fingolimod have occurred within the first 9 months after fingolimod initiation, but tumefactive MS may occur at any point during treatment. Cases of tumefactive MS have also been reported within the first 4 months after fingolimod discontinuation. Tumefactive MS should be considered when a severe MS relapse occurs during fingolimod treatment, especially during initiation, or after discontinuation of fingolimod, prompting imaging evaluation and initiation of appropriate treatment.

5.11 Increased Blood Pressure

In adult MS controlled clinical trials, patients treated with fingolimod 0.5 mg had an average increase over placebo of approximately 3 mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure, first detected after approximately 1 month of treatment initiation, and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on fingolimod 0.5 mg and in 4% of patients on placebo. Blood pressure (BP) should be monitored during treatment with fingolimod.

5.12 Malignancies

Cutaneous Malignancies

The risk of basal cell carcinoma (BCC) and melanoma is increased in patients treated with fingolimod. In two-year placebo-controlled trials in adult patients, the incidence of BCC was 2% in patients on fingolimod 0.5 mg and 1% in patients on placebo [see Adverse Reactions (6.1)]. Melanoma, squamous cell carcinoma and Merkel cell carcinoma have been reported with fingolimod in the postmarketing setting. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Lymphoma

Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving fingolimod. The reporting rate of non- Hodgkin lymphoma with fingolimod is greater than that expected in the general population adjusted by age, gender, and region. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported with fingolimod in the postmarketing setting.

5.13 Immune System Effects Following Fingolimod Discontinuation

Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of fingolimod. Lymphocyte counts generally return to the normal range within 1 to 2 months of stopping therapy [see Clinical Pharmacology (12.2)]. Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects) [see Drug Interactions (7.4)].

5.14 Hypersensitivity Reactions

Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported with fingolimod in the postmarketing setting. Fingolimod is contraindicated in patients with history of hypersensitivity to fingolimod or any of its excipients [see Contraindications (4)].

 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](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 Progressive Multifocal Leukoencephalopathy (PML): Withhold fingolimod at the first sign or symptom suggestive of PML. ([5.3](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 Macular Edema: Examine the fundus before and 3 to 4 months after treatment start. Diabetes mellitus and uveitis increase the risk. ([5.4](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

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](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx), [8.6](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx), [12.3](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 Posterior Reversible Encephalopathy Syndrome (PRES): If suspected, discontinue fingolimod. ([5.6](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 Respiratory Effects: Evaluate when clinically indicated. ([5.7](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 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](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 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 during treatment. ([5.11](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

 Malignancies: Suspicious skin lesions should be evaluated. ([5.12](http://file:///Z:%5CUS%20CMC%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.25%20and%200.5%20mg%5CRLD%20Update%20August%202023%5CProposed%20PI-clean.docx))

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies, fingolimod may cause fetal harm when administered to a pregnant woman. Data from prospective reports to the Fingolimod Pregnancy Registry are currently not sufficient to allow for an adequate assessment of the drug-associated risk for birth defects and miscarriage in humans.

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 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 because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping fingolimod, patients had stopped fingolimod because of pregnancy or planned pregnancy [see Warnings and Precautions (5.9)].

Data

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 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/m2 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 fingolimod and any potential adverse effects on the breastfed infant from fingolimod 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 fingolimod [see Use in Specific Populations (8.1)].

Contraception

Before initiation of fingolimod 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 fingolimod [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 fingolimod 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 (fingolimod 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 fingolimod 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-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 fingolimod therapy.

Safety and effectiveness of fingolimod 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 fingolimod did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Fingolimod 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), 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 fingolimod 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

Fingolimod 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 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Oral carcinogenicity studies of fingolimod were conducted in mice and rats. In mice, fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant lymphoma was increased in males and females at the mid and high dose. The lowest dose tested (0.025 mg/kg/day) is less than the RHD of 0.5 mg/day on a body surface area (mg/m2) basis. In rats, fingolimod was administered at oral doses of 0, 0.05, 0.15, 0.5, and 2.5 mg/kg/day. No increase in tumors was observed. The highest dose tested (2.5 mg/kg/day) is approximately 50 times the RHD on a mg/m2 basis.

Fingolimod was negative in a battery of in vitro (Ames, mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.

When fingolimod was administered orally (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested (10 mg/kg), which is approximately 200 times the RHD on a mg/m2 basis.

13.2 Animal Toxicology and/or Pharmacology

Lung toxicity was observed in 2 different strains of rats and in dogs and monkeys. The primary findings included increase in lung weight, associated with smooth muscle hypertrophy, hyperdistention of the alveoli, and/or increased collagen. Insufficient or lack of pulmonary collapse at necropsy, generally correlated with microscopic changes, was observed in all species. In rats and monkeys, lung toxicity was observed at all oral doses tested in chronic studies. The lowest doses tested in rats (0.05 mg/kg/day in the 2-year carcinogenicity study) and monkeys (0.5 mg/kg/day in the 39-week toxicity study) are similar to and approximately 20 times the RHD on a mg/m2 basis, respectively.

In the 52-week oral study in monkeys, respiratory distress associated with ketamine administration was observed at doses of 3 and 10 mg/kg/day; the most affected animal became hypoxic and required oxygenation. As ketamine is not generally associated with respiratory depression, this effect was attributed to fingolimod. In a subsequent study in rats, ketamine was shown to potentiate the bronchoconstrictive effects of fingolimod. The relevance of these findings to humans is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Fingolimod capsules 0.5 mg are 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.

Fingolimod capsules are supplied as follows:

Bottle of 30 with child-resistant closure, NDC 68462-166-30

Carton of 28 capsules containing 2 cartons of 14 capsules per blister card NDC 68462-166-15

Carton of 7 capsules containing 1 blister card of 7 capsules per blister card NDC 68462-166-07

16.2 Storage and Handling

Fingolimod capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

2 DOSAGE AND ADMINISTRATION

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)].

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 are 0.5 mg orally once- daily.

Fingolimod capsules 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.

Assessments are required prior to initiating fingolimod capsules ([2.1](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc))

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](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc), [2.3](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc))

First-Dose Monitoring (including reinitiation after discontinuation greater than 14 days and dose increases):

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](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc))

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](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc))

Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. ([2.4](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc))

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](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc), [7.1](http://file:///X:%5C5%20US%20Labelling%5C2.%20US%20Products_Submissions%5CFingolimod%20Capsules,%200.5%20mg%5C00xx%20-%20CR%20-%20RLD%20update%20Aug%202019%20-TA%20Package%5CWorking%20docs%5CPI%5CJan%203%202020%20-%20New%20RLD%20update%20Dec%202020%5CProposed%20PI.doc))