Gilenya (fingolimod) capsules 0.5 mg

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)  

August 2015

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Progressive Multifocal Leukoencephalopathy
  • A case of progressive multifocal leukoencephalopathy (PML) and a case of probable PML occurred in patients with MS who received GILENYA in the post marketing 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. One patient developed PML after taking GILENYA for approximately 2.5 years. The other patient developed probable PML after taking GILENYA for approximately 4 years. The diagnosis of probable PML was based on MRI findings and the detection of JCV DNA in the CSF in the absence of clinical signs or symptoms specific to PML. The patients had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patients were also not taking any immunosuppressive or immunomodulatory medications concomitantly…


July 2015

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  • *Addition of information with respect to cryptococcal infections, including cases of cryptococcal meningitis


May 2015

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Bradyarrhythmia and Atrioventricular Blocks

Reduction in Heart Rate

  • edited...In controlled clinical trials, 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.

Atrioventricular Blocks section edited

  • Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, 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.

Risk of Infections

  • added...a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available
  • edited...In MS placebo-controlled trials, 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.

Herpes Viral Infections section added

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

Varicella Zoster Virus Antibody Testing/Vaccination section edited

Macular Edema section edited
  • Fingolimod increases the risk of macular edema. Perform an examination of the fundus including the macula in all patients before starting treatment, again 3–4 months after starting treatment, and again at any time after a patient reports visual disturbances while on GILENYA therapy.
  • 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 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 0.5 mg 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. A decision on whether or not to discontinue GILENYA 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 GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the combined clinical trial experience 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. GILENYA 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 3–4 months after starting treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.
Respiratory Effects section edited
  • 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, 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, 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.
Liver Injury
  • added...In 2-year placebo-controlled clinical trials, elevation of liver transaminases 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.


April 2014

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5.4 Posterior Reversible Encephalopathy Syndrome
  • new section added

May 2012

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  • Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure
  • History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker
  • Baseline QTc interval ≥500 ms
  • Treatment with Class Ia or Class III anti-arrhythmic drugs


5.1 Bradyarrhythmia and Atrioventricular Blocks
  • Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA treatment initiation [see Dosage and Administration (2)]. 

Reduction in heart rate

  • After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours .....

Post-marketing experience

  • In the post-marketing setting, third degree AV block and AV block with junctional escape have been observed during the first-dose six-hour observation period .....


QT prolonging drugs 
  • GILENYA has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility [see Dosage and Administration (2) and Warnings and Precautions (5.1)].
  • The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. 
Drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers or diltiazem)
  • Experience with GILENYA in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction (e.g., beta blockers, digoxin, or heart-rate slowing calcium channel blockers such as diltiazem or verapamil) is limited. Because initiation of GILENYA treatment may result in .....


17.2 Cardiac Effects
  • Advise patients that initiation of GILENYA treatment results in a transient decrease in heart rate. Inform patients that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose. Advise patients that if GILENYA is discontinued for more than 14 days, effects similar to those observed on treatment initiation may be seen and observation for at least 6 hours will be needed on treatment re-initiation, and that the same precautions will be taken if treatment is interrupted for more than one day within the first 2 weeks of treatment, or for more than 7 days during week 3 and 4 of treatment


Extensive changes to:
  • What is the most important information I should know about GILENYA?
  • Who should not take GILENYA? 
  • What should I tell my doctor before taking GILENYA?
  • How should I take GILENYA?


July 2011

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5.5 Hepatic Effects
  • "...the majority of elevations...within 3-4 months" is changed to "...occurred within 6-9 months."


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