5 WARNINGS AND PRECAUTIONS

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

5.1 Bradyarrhythmia and Atrioventricular Blocks

Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during GILENYA treatment initiation [see Dosage and Administration (2.4)] .

Reduction in Heart Rate

After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 bpm in adults, and below 50 bpm in pediatric patients occurred rarely. In controlled clinical trials in adult patients, adverse reactions of symptomatic bradycardia following the first dose were reported in 0.6% of patients receiving GILENYA 0.5 mg and in 0.1% of patients on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain that usually resolved within the first 24 hours on treatment.

Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility after the first dose.

Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (> 450 msec adult and pediatric males, > 470 msec adult females, or > 460 msec pediatric females) before dosing or during 6-hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility.

Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. Clinical data indicate effects of GILENYA on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms.

Atrioventricular Blocks

Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials in adult patients, first-degree AV block after the first dose occurred in 4.7% of patients receiving GILENYA and 1.6% of patients on placebo. In a study of 697 patients with available 24-hour Holter monitoring data after their first dose (N = 351 receiving GILENYA and N = 346 on placebo), second-degree AV blocks (Mobitz Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N = 14) of patients receiving GILENYA and 2% (N = 7) of patients on placebo. Of the 14 patients receiving GILENYA, 7 patients had 2:1 AV block (5 patients within the first 6 hours postdose and 2 patients after 6 hours postdose). All second-degree AV blocks on placebo were Mobitz Type I and occurred after the first 12 hours postdose. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol.

Postmarketing Experience

In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA.

5.2 Infections

Risk of Infections

GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature [see Clinical Pharmacology (12.2)] . Life-threatening and fatal infections have occurred in association with GILENYA.

Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved.

In MS placebo-controlled trials in adult patients, the overall rate of infections (72%) with GILENYA was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in GILENYA-treated patients. Serious infections occurred at a rate of 2.3% in the GILENYA 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 GILENYA. 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 GILENYA 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 GILENYA in the postmarketing setting. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving GILENYA 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 GILENYA in the postmarketing setting. Cryptococcal infections have generally occurred after approximately 2 years of GILENYA 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 GILENYA did not receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA 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 GILENYA 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 GILENYA. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA 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 GILENYA in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation with GILENYA, 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 GILENYA 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. Longer treatment duration increases the risk of PML in GILENYA-treated patients; the majority of cases have occurred in patients treated with GILENYA for at least 18 months.

At the first sign or symptom suggestive of PML, withhold GILENYA 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 resonance 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 GILENYA. 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 GILENYA should be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including GILENYA, 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

S1P receptor modulators, including GILENYA, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with GILENYA. Perform an examination of the fundus, including the macula, 3 to 4 months after starting treatment, periodically while on therapy, and any time there is a change in vision.

A dose-dependent increase in the risk of macular edema occurred in the GILENYA 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 GILENYA 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 GILENYA in the postmarketing setting, usually within the first 6 months of treatment.

Continuation of GILENYA in patients who develop macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing GILENYA if macular edema develops; this decision 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 GILENYA therapy. In the combined clinical trial experience in adult patients with all doses of fingolimod, the rate of macular edema was higher in MS patients with a history of uveitis compared to those without a history of uveitis (approximately 20% versus 0.6%, respectively). GILENYA has not been tested in MS patients with diabetes mellitus.

5.5 Liver Injury

Clinically significant liver injury has occurred in patients treated with GILENYA 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 GILENYA 0.5 mg and 3% of patients on placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on GILENYA and 1% of patients on placebo. The majority of elevations occurred within 6 to 9 months. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

Prior to starting treatment with GILENYA (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 GILENYA 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 GILENYA 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 GILENYA 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 GILENYA. 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, GILENYA 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 GILENYA 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 GILENYA 0.5 mg and 1.0% 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 GILENYA 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 GILENYA 0.5 mg and 7% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA 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 GILENYA if clinically indicated.

5.8 Fetal Risk

GILENYA 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.

Available observational pregnancy registry data suggest that use of GILENYA is associated with an increased prevalence of major birth defects in comparison to the general population.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate GILENYA from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment [see Use in Specific Populations (8.1, 8.3)] .

5.9 Severe Increase in Disability After Stopping GILENYA

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

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

After stopping GILENYA 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 GILENYA therapy and after GILENYA discontinuation in the postmarketing setting. Most reported cases of tumefactive MS in patients receiving GILENYA have occurred within the first 9 months after GILENYA 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 GILENYA discontinuation. Tumefactive MS should be considered when a severe MS relapse occurs during GILENYA treatment, especially during initiation, or after discontinuation of GILENYA, prompting imaging evaluation and initiation of appropriate treatment.

5.11 Increased Blood Pressure

Increases in blood pressure have been observed in patients treated with GILENYA.

In adult MS controlled clinical trials, patients treated with GILENYA 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 GILENYA 0.5 mg and in 4% of patients on placebo.

Monitor blood pressure (BP) in adult and pediatric patients during treatment with GILENYA.

5.12 Malignancies

Cutaneous Malignancies

The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma) is increased in patients treated with S1P receptor modulators. Use of GILENYA has been associated with an increased risk of BCC and melanoma.

In two-year placebo-controlled trials in adult patients, the incidence of BCC was 2% in patients on GILENYA 0.5 mg and 1% in patients on placebo [see Adverse Reactions (6.1)] . Melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma [see Warnings and Precautions (5.2)] , and Merkel cell carcinoma have been reported with GILENYA in the postmarketing setting.

Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter 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. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking GILENYA.

Lymphoma

Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving GILENYA. The reporting rate of non-Hodgkin lymphoma with GILENYA 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 GILENYA in the postmarketing setting.

5.13 Immune System Effects Following GILENYA Discontinuation

Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of GILENYA. 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 GILENYA in the postmarketing setting. GILENYA is contraindicated in patients with history of hypersensitivity to fingolimod or any of its excipients [see Contraindications (4)] .

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