NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`GILENYA™ safely and effectively. See full prescribing information for
`
`
`GILENYA.
`
`
`
`
`GILENYA (fingolimod) capsules
`
`Initial U.S. Approval: 2010
`
`
`
`--------------INDICATIONS AND USAGE---------------------
`GILENYA is a sphingosine 1-phosphate receptor modulator indicated for the
`treatment of patients with relapsing forms of multiple sclerosis to reduce the
`frequency of clinical exacerbations and to delay the accumulation of physical
`disability. (1)
`
`
`------------DOSAGE AND ADMINISTRATION-------------
`
`Recommended dose: 0.5 mg orally once daily, with or without food. (2)
`
`
`-----------DOSAGE FORMS AND STRENGTHS------------
`
`0.5 mg hard capsules. (3)
`
`
`---------------------CONTRAINDICATIONS-------------------
`None. (4)
`
`
`---------------WARNINGS AND PRECAUTIONS------------
`• Decrease in heart rate and/or atrioventricular conduction after first dose of
`
`GILENYA: Observe all patients for signs and symptoms of bradycardia
`
`for 6 hours after first dose. Obtain baseline ECG before first dose if not
`recently available in those at higher risk of bradyarrhythmia. Patients
`
`
`receiving Class Ia or Class III antiarrhythmic drugs, beta blockers, calcium
`channel blockers, those with a low heart rate, history of syncope, sick sinus
`syndrome, 2nd degree or higher conduction block, ischemic heart disease,
`or congestive heart failure are at increased risk of developing bradycardia
`
`or heart blocks. (5.1)
`• Infections: GILENYA may increase the risk of infections. A recent CBC
`
`should be available before initiating treatment with GILENYA. Monitor
`for signs and symptoms of infection during treatment and for two months
`after discontinuation. Do not start GILENYA treatment in patients with
`active acute or chronic infections. (5.2)
`• Macular edema: Can occur with or without visual symptoms. An
`
`
`ophthalmologic evaluation should be performed before starting GILENYA
`and at 3-4 months after treatment initiation. Monitor visual acuity at
`baseline and during routine evaluations of patients. Patients with diabetes
`mellitus or a history of uveitis are at increased risk and should have regular
`
`ophthalmologic evaluations. (5.3)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Bradyarrhythmia and Atrioventricular Blocks
`
`5.2 Infections
`
`5.3 Macular Edema
`
`5.4 Respiratory Effects
`
`
`5.5 Hepatic Effects
`
`
`5.6 Fetal Risk
`
`
`5.7 Blood Pressure Effects
`
`5.8 Immune System Effects Following GILENYA Discontinuation
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Hepatic Impairment
`
`
`
`
`
`
`
`
`
`Page 1
`
`• Decrease in pulmonary function tests with GILENYA: Obtain
`
`spirometry and diffusion lung capacity for carbon monoxide (DLCO)
`
`when clinically indicated. (5.4)
`• Hepatic effects: GILENYA may increase liver transaminases. Recent
`
`
`liver enzyme results should be available before initiating treatment with
`GILENYA. Assess liver enzymes if symptoms suggestive of hepatic
`injury develop. Discontinue GILENYA if significant liver injury is
`
`confirmed. (5.5)
`
`• Fetal risk: Women of childbearing potential should use effective
`
`contraception during and for two months after stopping GILENYA
`treatment. (5.6)
`
`
`
`-------------------ADVERSE REACTIONS----------------------
`Most common adverse reactions (incidence ≥10% and > placebo):
`Headache, influenza, diarrhea, back pain, liver transaminase elevations and
`cough. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-332-
`1088 or www.fda.gov/medwatch.
`
`
`-------------------DRUG INTERACTIONS---------------------
`• Class Ia or Class III antiarrhythmic drugs: Because of a risk of serious
`
`rhythm disturbances, carefully monitor patients on Class Ia or Class III
`
`
`antiarrhythmic drugs during initiation of therapy. (5.1, 7)
`
`• Beta blockers: Because of a risk of additive effect on heart rate,
`
`carefully monitor patients on beta blockers during initiation of therapy.
`(5.1, 7)
`• Ketoconazole: Monitor patients closely, as GILENYA exposure is
`
`
`increased by70% during concomitant use with systemic ketoconazole,
`and risk of adverse reactions is greater. (7, 12.3)
`
`• Vaccines: Avoid live attenuated vaccines during, and for 2 months after
`
`stopping GILENYA treatment, due to risk of infection. (5.2, 7)
`
`
`
`
`
`-------------USE IN SPECIFIC POPULATIONS-------------
`• Pregnancy: Based on animal data, may cause fetal harm. Pregnancy
`
`
`
`registry available. (8.1)
`• Pediatric patients: Safety and effectiveness have not been established.
`
`
`(8.4)
`• Hepatic impairment: Monitor patients with severe hepatic impairment
`
`closely, as GILENYA exposure is doubled, and risk of adverse
`reactions is greater. (5.5, 8.5, 12.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide
`
`
`
`
`
`
`
`
`
`Revised: 09/2010
`
`
`8.7 Renal Impairment
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Benefits and Risks
`
`17.2 Cardiac Effects
`
`17.3 Risk of Infections
`
`17.4 Macular Edema
`
`
`17.5 Respiratory Effects
`
`17.6 Hepatic Effects
`
`17.7 Fetal Risk
`
`17.8 Persistence of GILENYA effects after drug discontinuation
`* Sections or subsections omitted from the full prescribing information are
`
`
`not listed
`
`Biogen Exhibit 2137
`Mylan v. Biogen
`IPR 2018-01403
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`NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
`
`FULL PRESCRIBING INFORMATION
`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
`
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`Page 3
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`NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
`
`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
`evaluation 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 evaluation 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.
`
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`Page 4
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`NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
`
`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. 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 evaluation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic evaluations
`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 evaluation of respiratory function and evaluation 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 3-4 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
`
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`Page 5
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`NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
`
`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).
`Table 1 Adverse Reactions in Study 1 (occurring in ≥1% of patients, and reported for GILENYA 0.5 mg at ≥1%
`higher rate than for placebo)
`
`
`
`Primary System Organ Class
`Preferred Term
`
`
`Infections
` Influenza viral infections
`Herpes viral infections
`
`Bronchitis
`Sinusitis
`
`
` Gastroenteritis
`Tinea infections
`
`Cardiac Disorders
`
`Bradycardia
`Nervous system disorders
` Headache
` Dizziness
`
` Paresthesia
`Migraine
`Gastrointestinal disorders
`
`Diarrhea
`General disorders and administration site
`conditions
`
`Asthenia
`
`
`
`GILENYA 0.5 mg
`N=425
`%
`
`
`13
`9
`8
`7
`5
`4
`
`4
`
`25
`7
`5
`5
`
`12
`
`
`3
`
`Placebo
`N=418
`%
`
`
`10
`8
`4
`5
`3
`1
`
`1
`
`23
`6
`4
`1
`
`7
`
`
`1
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`NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
`
`
`
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`
`
`
`
`Page 6
`
`GILENYA 0.5 mg
`N=425
`%
`
`
`
`12
`
`4
`3
`3
`
`14
`5
`5
`3
`
`
`Placebo
`N=418
`%
`
`
`
`7
`
`2
`2
`1
`
`5
`1
`3
`1
`
`
` Primary System Organ Class
`
`Preferred Term
`
`
`Musculoskeletal and connective tissue
`disorders
`
`Back pain
`Skin and subcutaneous tissue disorders
`Alopecia
` Eczema
`Pruritus
`Investigations
` ALT/AST increased
` GGT increased
` Weight decreased
`
`Blood triglycerides increased
`Respiratory, thoracic and mediastinal
`disorders
`Cough
` Dyspnea
`Psychiatric disorders
`Depression
`Eye disorders
` Vision blurred
`
` Eye pain
`Vascular disorders
`
`Hypertension
`Blood and lymphatic system disorders
`
` Lymphopenia
`Leukopenia
`
`
`
`10
`8
`
`8
`
`4
`3
`
`6
`
`4
`3
`
`8
`5
`
`7
`
`1
`1
`
`4
`
`1
`<1
`
`
`
`Adverse reactions in Study 2, a 1-year active-controlled (vs. interferon beta-1a, n=431) study including 849 patients with
`MS treated with fingolimod, were generally similar to those in Study 1.
`Vascular Events
`Vascular events, including ischemic and hemorrhagic strokes, peripheral arterial occlusive disease and posterior reversible
`
`
`encephalopathy syndrome were reported in premarketing clinical trials in patients who received GILENYA doses (1.25-5
`mg) higher than recommended for use in MS. No vascular events were observed with GILENYA 0.5 mg in the
`premarketing database.
`Lymphomas
`Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in
`premarketing clinical trials in MS patients receiving GILENYA at, or above, the recommended dose of 0.5 mg. Based on
`the small number of cases and short duration of exposure, the relationship to GILENYA remains uncertain.
`
`7 DRUG INTERACTIONS
`Class Ia or Class III antiarrhythmic drugs
`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. Since initiation of GILENYA
`treatment results in decreased heart rate, patients on Class Ia or Class III antiarrhythmic drugs should be closely monitored
`[see Warnings and Precautions (5.1)].
`Ketoconazole
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`Page 7
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`NDA 02257 - FDA Approved Labeling Text dated September 21, 2010
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` The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when coadministered with
`
`
` ketoconazole. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the
`risk of adverse reactions is greater.
`
` Vaccines
`Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA [see
`Clinical Pharmacology (12.2)]. The use of live attenuated vaccines should be avoided during and for 2 months after
`
` treatment with GILENYA because of the risk of infection.
`Antineoplastic, immunosuppressive or immunomodulating therapies
`Antineoplastic, immunosuppressive or immune modulating therapies are expected to increase the risk of
`
` immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as
`natalizumab or mitoxantrone.
`
`Heart rate-lowering drugs (e.g., beta blockers or diltiazem)
`Experience with GILENYA in patients receiving concurrent therapy with beta blockers is limited. These patients should
`
`
`be carefully monitored during initiation of therapy. When GILENYA is used with atenolol, there is an additional 15%
`reduction of heart rate upon GILENYA initiation, an effect not seen with diltiazem [see Warnings and Precautions (5.1)].
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`
`
`Laboratory test interaction
`Because GILENYA reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood
`lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with GILENYA. A
`recent CBC should be available before initiating treatment with GILENYA.
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C
`There are no adequate and well-controlled studies in pregnant women. In oral studies conducted in rats and rabbits,
`
`fingolimod demonstrated developmental toxicity, including teratogenicity (rats) and embryolethality, when given to
`pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose (RHD) of 0.5 mg/day on
`a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats included 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. Because it takes approximately 2 months to eliminate
`fingolimod from the body, potential risks to the fetus may persist after treatment ends [see Warnings and Precautions
`
`(5.7, 5.8)]. GILENYA should be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
`Pregnancy Registry
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`
`
`A pregnancy registry has been established to collect information about the effect of GILENYA use during pregnancy.
`Physicians are encouraged to enroll pregnant patients, or pregnant women may enroll themselves in the GILENYA
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`pregnancy registry by calling 1-877-598-7237.
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`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 embryo-fetal deaths were
`observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the 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
`embryo-fetal 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.
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`8.2 Labor and Delivery
`The effects of GILENYA on labor and delivery are unknown.
`8.3 Nursing Mothers
`Fingolimod is excreted in the milk of treated rats. It is not known whether this drug is excreted in human milk. Because
`many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
`
`GILENYA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the
`importance of the drug to the mother.
`8.4 Pediatric Use
`The safety and effectiveness of GILENYA in pediatric patients with MS below the age of 18 have not been established.
`8.5 Geriatric Use
`Clinical MS studies of GILENYA did not include sufficient numbers of patients aged 65 years and over to determine
`whether they respond differently than younger patients. GILENYA 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) and 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 GILENYA 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
`No cases of overdosage have been reported. However, single doses up to 80-fold the recommended dose (0.5 mg) resulted
`in no clinically significant adverse reactions. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which
`
`was clinically consistent with small airway reactivity.
`
`Neither dialysis nor plasma exchange results in removal of fingolimod from the body.
`11 DESCRIPTION
`Fingolimod is a sphingosine 1-phosphate receptor modulator.
`
`Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride. Its structure is shown below:
`
`
`
`Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in
`propylene glycol. It has a molecular weight of 343.93.
`GILENYA is provided as 0.5 mg hard gelatin capsules for oral use. Each capsule contains 0.56 mg of fingolimod
`hydrochloride, equivalent to 0.5 mg of fingolimod.
`Each GILENYA 0.5 mg capsule contains the following inactive ingredients: gelatin, magnesium stearate, mannitol,
`titanium dioxide, yellow iron oxide.
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` 12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate
`
`is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3,
`
`4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of
`lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is
`
`unknown, but may involve reduction of lymphocyte migration into the central nervous system.
`
`12.2 Pharmacodynamics
`Heart rate and rhythm
`Fingolimod causes a transient reduction in heart rate and AV co