 Treatment with Class Ia or Class III anti-arrhythmic drugs (4)
` Hypersensitivity to fingolimod or its excipients (4)
`
`------------------------WARNINGS AND PRECAUTIONS--------------------
` Infections: GILENYA may increase the risk. Obtain a 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: Examine the fundus before and 3–4 months after
`treatment start. Diabetes mellitus and uveitis increase the risk. (5.4)
` Posterior reversible encephalopathy syndrome (PRES): If suspected,
`discontinue GILENYA. (5.5)
` Respiratory effects: Evaluate when clinically indicated. (5.6)
` Liver injury: Obtain liver enzyme results before initiation. Closely
`monitor patients with severe hepatic impairment. Discontinue if
`significant liver injury occurs. (5.7, 8.6, 12.3)
` Fetal risk: Women of childbearing potential should use effective
`contraception during and for 2 months after stopping GILENYA. (5.8)
` Increased blood pressure (BP): Monitor BP during treatment. (5.9)
` Basal cell carcinoma: suspicious skin lesions should be evaluated. (5.10)
`
`-------------------------------ADVERSE REACTIONS---------------------------
`Most common adverse reactions (incidence ≥10% and > placebo): Headache,
`liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain,
`abdominal pain, and pain in extremity (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-
`FDA-1088 or www.fda.gov/medwatch.
`
`--------------------------------DRUG INTERACTIONS--------------------------
` Systemic ketoconazole: Monitor during concomitant use. (7, 12.3)
` Vaccines: Avoid live attenuated vaccines during, and for 2 months after
`stopping GILENYA treatment. (5.2, 7)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`
`
`
`
`Revised: 2/2016
`
`
`
`
`
`Pregnancy
`8.1
`Labor and Delivery
`8.2
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`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
`* Sections or subsections omitted from the full prescribing information are
`not listed.
`
`
`
`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, for oral use
`Initial U.S. Approval: 2010
`
`----------------------------RECENT MAJOR CHANGES-----------------------------
`Contraindications (4)
`2/2016
`Warnings and Precautions (5.1, 5.4, 5.6)
`5/2015
`Warnings and Precautions (5.2, 5.3, 5.7, 5.10, 5.12)
`2/2016
`
`---------------------------INDICATIONS AND USAGE-------------------------------
`GILENYA is a sphingosine 1-phosphate receptor modulator indicated for 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. (1)
`
`-------------------------DOSAGE AND ADMINISTRATION----------------------------
` Recommended dose: 0.5 mg orally once-daily, with or without food (2)
` First Dose Monitoring (including re-initiation after discontinuation >14 days):
`o 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)
`o Monitor until resolution if heart rate <45 bpm, atrioventricular (AV) block, or
`if lowest postdose heart rate is at the end of the observation period. (2)
`o Monitor symptomatic bradycardia with ECG until resolved. Continue
`overnight if intervention is required; repeat first-dose monitoring for second
`dose. (2)
`o 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, 7)
`
`-------------------------DOSAGE FORMS AND STRENGTHS-------------------------
`0.5 mg hard capsules (3)
`
`-----------------------------------CONTRAINDICATIONS--------------------------------
` Recent myocardial infarction, unstable angina, stroke, transient ischemic attack,
`decompensated heart failure with hospitalization, or Class III/IV heart failure (4)
` History of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus
`syndrome, unless patient has a pacemaker (4)
` Baseline QTc interval ≥500 msec (4)
`
`
`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
`Progressive Multifocal Leukoencephalopathy
`5.4 Macular Edema
`5.5
`Posterior Reversible Encephalopathy Syndrome
`5.6 Respiratory Effects
`5.7
`Liver Injury
`5.8
`Fetal Risk
`5.9
`Increased Blood Pressure
`5.10 Basal Cell Carcinoma
`5.11
`Immune System Effects Following GILENYA Discontinuation
`5.12 Hypersensitivity Reactions
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`Page 1 of 25
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`Biogen Exhibit 2072
`Coalition v. Biogen
`IPR2015-01993
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`

`
`
`
`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
`
`Recommended Dose
`
`The recommended dose of GILENYA is 0.5 mg orally once-daily. 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.
`Patients who initiate GILENYA and those who re-initiate treatment after discontinuation for longer than 14 days require
`first dose monitoring [see Reinitiation of Therapy Following Discontinuation].
`
`First Dose Monitoring
`
`Initiation of GILENYA treatment results in a decrease in heart rate [see Warnings and Precautions (5.1) and Clinical
`Pharmacology (12.2)]. After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 nadir
`generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in
`some patients.
`
`The first dose of GILENYA should be administered in a setting in which resources to appropriately manage symptomatic
`bradycardia are available. In order to assess patient response to the first dose of fingolimod, observe all patients for 6
`hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an
`electrocardiogram (ECG) prior to dosing, and at the end of the observation period.
`
`Additional observation should be instituted until the finding has resolved in the following situations:
`
` The heart rate 6 hours postdose is <45 bpm
` 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
`
`Should postdose symptomatic bradycardia occur, initiate appropriate management, begin continuous ECG monitoring,
`and continue observation until the symptoms have resolved.
`
`Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring
`in a medical facility should be instituted, and the first dose monitoring strategy should be repeated after the second dose of
`GILENYA.
`
`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. GILENYA is contraindicated in patients who in the last 6 months experienced myocardial infarction,
`unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class
`III/IV heart failure [see Contraindications (4)].
`
`Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a
`prolonged QTc interval (>450 msec males, >470 msec 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 [see
`Drug Interactions (7)].
`
`Experience with GILENYA is limited in patients receiving concurrent therapy with drugs that slow heart rate or
`atrioventricular conduction (e.g., beta blockers, heart-rate lowering calcium channel blockers such as diltiazem or
`verapamil, or digoxin). Because the initiation of GILENYA treatment is also associated with slowing of the heart rate,
`
`
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`Page 2 of 25
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`

`
`
`concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. The
`possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction should be evaluated by the
`physician prescribing these drugs before initiating GILENYA. Patients who cannot switch should have overnight
`continuous ECG monitoring after the first dose [see Drug Interactions (7)].
`
`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.
`
`Reinitiation of Therapy Following Discontinuation
`
`If GILENYA therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and
`AV conduction may recur on reintroduction of GILENYA treatment and the same precautions (first dose monitoring) as
`for initial dosing should apply. 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.
`
`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 2 radial bands imprinted on the capsule body with yellow ink.
`
`4
`
`CONTRAINDICATIONS
`
` 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 msec
`
` Treatment with Class Ia or Class III anti-arrhythmic drugs
`
` Patients who have had a hypersensitivity reaction to fingolimod or any of the excipients in GILENYA. Observed
`reactions include rash, urticaria and angioedema upon treatment initiation [see Warnings and Precautions (5.12)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`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 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 beats per minute were rarely observed. 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. 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.
`
`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.
`
`Atrioventricular Blocks
`
`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
`
`
`
`Page 3 of 25
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`

`
`
`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)].
`
`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, 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, 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 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. One of these events was
`fatal. 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 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
`
`
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`
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`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)].
`
`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 varicella zoster virus (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.
`
`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,
`and who were also not taking any immunosuppressive or immunomodulatory medications concomitantly. The patients
`had no other ongoing identified systemic medical conditions resulting in compromised immune system function, although
`one patient had a history of cancer treated with chemotherapy several years prior to taking Gilenya. The cases have
`occurred in patients treated with GILENYA 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 GILENYA and perform an appropriate diagnostic evaluation.
`MRI findings may be apparent before clinical signs or symptoms. 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.
`
`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 3–4 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 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.
`
`
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`
`
`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.
`
`5.5
`
`Posterior Reversible Encephalopathy Syndrome
`
`There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in 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.
`
`5.6
`
`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, 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.
`
`Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with
`GILENYA if clinically indicated.
`
`5.7
`
`Liver Injury
`
`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.
`
`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.
`
`Cases of liver injury with hepatocellular and/or cholestatic hepatitis have been reported with GILENYA in the
`postmarketing setting.
`
`Liver enzymes and bilirubin 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 preexisting 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 (8.6), Clinical Pharmacology
`(12.3)].
`
`
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`
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`5.8
`
`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.
`
`5.9
`
`Increased Blood Pressure
`
`In 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. Blood pressure should be
`monitored during treatment with GILENYA.
`
`5.10 Basal Cell Carcinoma
`
`Basal cell carcinoma (BCC) is associated with use of GILENYA. In two-year placebo-controlled trials the incidence of
`BCC was 2% in patients on GILENYA 0.5 mg and 1% in patients on placebo [see Adverse reactions (6)]. Providers and
`patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly
`evaluated.
`
`5.11
`
`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)].
`
`5.12 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)].
`
`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)]
` Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)]
` Macular Edema [see Warnings and Precautions (5.4)]
` Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.5)]
` Respiratory Effects [see Warnings and Precautions (5.6)]
` Liver Injury [see Warnings and Precautions (5.7)]
` Fetal Risk [see Warnings and Precautions (5.8)]
`
`Increased Blood Pressure [see Warnings and Precautions (5.9)]
` Basal Cell Carcinoma [see Warnings and Precautions (5.10)]
`
`Immune System Effects Following GILENYA Discontinuation [see Warnings and Precautions (5.11)]
` Hypersensitivity Reactions [see Warnings and Precautions (5.12)]
`
`6.1
`
`Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
`of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed
`in practice.
`
`In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received
`GILENYA 0.5 mg. This included 783 patients who received GILENYA 0.5 mg in the 2-year placebo-controlled trials
`(Studies 1 and 3) and 429 patients who received GILENYA 0.5 mg in the 1 year active-controlled trial (Study 2). The
`overall exposure in the controlled trials was equivalent to 1716 person-years. Approximately 1000 patients received at
`
`
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`least 2 years of treatment with GILENYA 0.5 mg. In all clinical studies, including uncontrolled extension studies, the
`exposure to GILENYA 0.5 mg was approximately 4119 person-years.
`
`In placebo-controlled trials, the most frequent adverse reactions (incidence ≥10% and >placebo) for GILENYA 0.5 mg
`were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in
`extremity. Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking
`GILENYA 0.5 mg were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1%
`compared to 0.5% on placebo).
`
`Table 1 lists adverse reactions that occurr