1 INDICATIONS AND USAGE

GILENYA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

2 DOSAGE AND ADMINISTRATION

The recommended dose of GILENYA is 0.5 mg orally once daily. Patients should be observed for 6 hours after the first dose to monitor for signs and symptoms of bradycardia [see Warnings and Precautions (5.1)]. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit.

GILENYA can be taken with or without food.

3 DOSAGE FORMS AND STRENGTHS

GILENYA is available as 0.5 mg hard capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and two radial bands imprinted on the capsule body with yellow ink.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Bradyarrhythmia and Atrioventricular Blocks

Reduction in heart rate

Initiation of GILENYA treatment results in a decrease in heart rate [see Clinical Pharmacology (12.2)]. Observe all patients for a period of 6 hours for signs and symptoms of bradycardia. Should post-dose bradyarrhythmia-related symptoms occur, initiate appropriate management and continue observation until the symptoms have resolved.

To identify underlying risk factors for bradycardia and atrioventricular (AV) block, if a recent electrocardiogram (i.e. within 6 months) is not available, obtain one in patients using anti-arrhythmics including beta-blockers and calcium channel blockers, those with cardiac risk factors, as described below, and those who on examination have a slow or irregular heart beat prior to starting GILENYA.

Experience with GILENYA in patients receiving concurrent therapy with beta blockers or in those with a history of syncope is limited. GILENYA has not been studied in patients with sitting heart rate less than 55 bpm. GILENYA has not been studied in patients with second degree or higher AV block, sick sinus syndrome, prolonged QT interval, ischemic cardiac disease, or congestive heart failure. GILENYA has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Class Ia and Class III antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.

After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 decline is maximal at approximately 6 hours. 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 one month of chronic treatment. The mean decrease in heart rate in patients on GILENYA 0.5 mg at 6 hours after the first dose was approximately 13 beats per minute (bpm). Heart rates below 40 bpm were rarely observed. Adverse reactions of bradycardia following the first dose were reported in 0.5% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced mild to moderate dizziness, fatigue, palpitations, and chest pain that resolved within the first 24 hours on treatment. 

Atrioventricular blocks

Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of first degree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Second degree AV blocks following the first dose were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5 mg and N=347 on placebo), second degree AV blocks, usually Mobitz type I (Wenckebach) were reported in 3.7% (N=13) of patients receiving GILENYA 0.5 mg and 2% (N=7) of patients on placebo. 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. One patient developed syncope and complete AV block following the first dose of fingolimod 1.25 mg (a dose higher than recommended) in an uncontrolled study.

Re-initiation of therapy following discontinuation

If GILENYA therapy is discontinued for more than two weeks the effects on heart rate and AV conduction may recur on reintroduction of GILENYA treatment and the same precautions as for initial dosing should apply. 

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)].

Before initiating treatment with GILENYA, a recent CBC (i.e. within 6 months) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to re-initiation of therapy. Because the elimination of fingolimod after discontinuation may take up to two 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.

Two patients died of herpetic infections during GILENYA controlled studies in the premarketing database (one disseminated primary herpes zoster and one herpes simplex encephalitis). In both cases, the patients were receiving a fingolimod dose (1.25 mg) higher than recommended for the treatment of MS (0.5 mg), and had received high dose corticosteroid therapy for suspected MS relapse. No deaths due to viral infections occurred in patients treated with GILENYA 0.5 mg in the premarketing database.

In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients.

Concomitant use with antineoplastic, immunosuppressive or immune modulating therapies

GILENYA has not been administered concomitantly with antineoplastic, immunosuppressive or immune modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies would be expected to increase the risk of immunosuppression [see Drug Interactions (7)].

Varicella zoster virus antibody testing/vaccination

As for any immune modulating drug, before initiating GILENYA therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered 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.

5.3 Macular Edema

In patients receiving GILENYA 0.5 mg, macular edema occurred in 0.4% of patients. An adequate ophthalmologic eva luation should be performed at baseline and 3-4 months after treatment initiation. If patients report visual disturbances at any time while on GILENYA therapy, additional ophthalmologic eva luation should be undertaken.

In MS controlled studies involving 1204 patients treated with GILENYA 0.5 mg and 861 patients treated with placebo, macular edema with or without visual symptoms was reported in 0.4% of patients treated with GILENYA 0.5 mg and 0.1% of patients treated with placebo; it occurred predominantly in the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmologic examination. Macular edema generally improved or resolved with or without treatment after drug discontinuation, but some patients had residual visual acuity loss even after resolution of macular edema. 

Continuation of GILENYA in patients who develop macular edema has not been eva luated. 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 eva luated.

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. The rate was approximately 20% in patients with a history of uveitis vs. 0.6% in those without a history of uveitis, in the combined experience with all doses of fingolimod. MS patients with diabetes mellitus or a history of uveitis should undergo an ophthalmologic eva luation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic eva luations while receiving GILENYA therapy. GILENYA has not been tested in MS patients with diabetes mellitus.

5.4 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. At Month 24, the reduction from baseline in the percent of predicted values for FEV1 was 3.1% for GILENYA 0.5 mg and 2% for placebo. For DLCO, the reductions from baseline in percent of predicted values at Month 24 were 3.8% for GILENYA 0.5 mg and 2.7% 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 controlled trials, dyspnea was reported in 5% of patients receiving GILENYA 0.5 mg and 4% 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 eva luation of respiratory function and eva luation of DLCO should be performed during therapy with GILENYA if clinically indicated.

5.5 Hepatic Effects  

Elevations of liver enzymes may occur in patients receiving GILENYA. Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of GILENYA therapy. 

During clinical trials, 3-fold the upper limit of normal (ULN) or greater elevation in liver transaminases occurred in 8% of patients treated with GILENYA 0.5 mg, as compared to 2% of patients on placebo. Elevations 5-fold the ULN occurred in 2% of patients on GILENYA and 1% of patients on placebo. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred with rechallenge in some patients, supporting a relationship to drug. The majority of elevations occurred within 6-9 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA.

Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.  GILENYA should be discontinued if significant liver injury is confirmed. Patients with pre-existing liver disease may be at increased risk of developing elevated liver enzymes when taking GILENYA. 

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 (8.5) and Clinical Pharmacology (12.3)].  

5.6 Fetal Risk

Based on animal studies, GILENYA may cause fetal harm. Because it takes approximately 2 months to eliminate GILENYA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment.

5.7 Blood Pressure Effects

In MS clinical trials, patients treated with GILENYA 0.5 mg had an average increase of approximately 2 mmHg in systolic pressure, and approximately 1 mmHg in diastolic pressure, first detected after approximately 2 months of treatment initiation, and persisting with continued treatment. In controlled studies involving 854 MS patients on GILENYA 0.5 mg and 511 MS patients on placebo, hypertension was reported as an adverse reaction in 5% of patients on GILENYA 0.5 mg and in 3% of patients on placebo. Blood pressure should be monitored during treatment with GILENYA. 

5.8 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 1-2 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)].

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)]
• Macular edema [see Warnings and Precautions (5.3)]
• Respiratory effects [see Warnings and Precautions (5.4)]
• Hepatic effects [see Warnings and Precautions (5.5)]

The most frequent adverse reactions (incidence ≥10% and > placebo) for GILENYA 0.5 mg were headache, influenza, diarrhea, back pain, liver enzyme elevations, and cough. The only adverse event leading to treatment interruption reported at an incidence >1% for GILENYA 0.5 mg was serum transaminase elevations (3.8%).  

6.1 Clinical Trials Experience

A total of 1703 patients on GILENYA (0.5 or 1.25 mg once daily) constituted the safety population in the 2 controlled studies in patients with relapsing remitting MS (RRMS) [see Clinical Studies (14)].

Study 1 was a 2-year placebo-controlled clinical study in 1272 MS patients treated with GILENYA 0.5 mg (n=425), GILENYA 1.25 mg (n=429) or placebo (n= 418).