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---------------------------------
`Indications and Usage (1)
`5/2018
`Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5)
`5/2018
`Warnings and Precautions (5.1, 5.11)
`5/2018
`Warnings and Precautions (5.2, 5.3)
`12/2017
`Warnings and Precautions (5.9)
`10/2018
`----------------------------INDICATIONS AND USAGE----------------------------------
`GILENYA is a sphingosine 1-phosphate receptor modulator indicated for the
`treatment of relapsing forms of multiple sclerosis (MS) in patients 10 years of age
`and older. (1)
`-------------------------DOSAGE AND ADMINISTRATION----------------------------
`• Assessments are required prior to initiating GILENYA (2.1)
`• Recommended dosage for adults and pediatric patients (10 years of age and
`older) weighing more than 40 kg: 0.5 mg orally once-daily, with or without food
`(2.2, 2.3)
`• Recommended dosage for pediatric patients (10 years of age and above)
`weighing less than or equal to 40 kg: 0.25 mg orally once-daily, with or without
`food (2.2, 2.3).
`• First Dose Monitoring (including re-initiation after discontinuation > 14 days and
`dose increases):
`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. (2.4)
`o Monitor until resolution if heart rate < 45 bpm in adults, < 55 bpm in patients
`aged 12 years and above, or < 60 bpm in pediatric patients aged 10 to below
`12 years, atrioventricular (AV) block, or if lowest postdose heart rate is at the
`end of the observation period. (2.4)
`o Monitor symptomatic bradycardia with ECG until resolved. Continue
`overnight if intervention is required; repeat first-dose monitoring for second
`dose. (2.4)
`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. (2.4, 7.1)
`-------------------------DOSAGE FORMS AND STRENGTHS-------------------------
`0.25 mg hard capsules (3)
`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)
`• 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)
`• Severe increase in disability after stopping GILENYA: Monitor for
`development of severe increase in disability following discontinuation
`and begin appropriate treatment as needed. (5.9)
`• Increased blood pressure (BP): Monitor BP during treatment. (5.10)
`• Cutaneous malignancies: Suspicious skin lesions should be evaluated.
`(5.11)
`-------------------------------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. (7.2, 12.3)
`• Vaccines: Avoid live attenuated vaccines during, and for 2 months after
`stopping GILENYA treatment. (5.2, 7.3)
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`
`
`
`
`
`
`Revised: 10/2018
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Assessment Prior to Initiating GILENYA
`2.2
`Important Administration Instructions
`2.3 Recommended Dosage
`2.4
`First-Dose Monitoring
`2.5 Monitoring After Reinitiation of Therapy Following
`Discontinuation
`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 Severe Increase in Disability after Stopping GILENYA
`5.10
`Increased Blood Pressure
`5.11 Cutaneous Malignancies
`5.12
`Immune System Effects Following GILENYA Discontinuation
`5.13 Hypersensitivity Reactions
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 QT Prolonging Drugs
`7.2 Ketoconazole
`
`7.3 Vaccines
`7.4 Antineoplastic, Immunosuppressive, or Immune-Modulating
`Therapies
`7.5 Drugs That Slow Heart Rate or Atrioventricular Conduction
`(e.g., beta blockers or diltiazem)
`7.6
`Laboratory Test Interaction
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`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
`14.1 Adults
`14.2 Pediatric Patients (10 to less than 18 Years of Age)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
`
`
`Reference ID: 4340211
`
`Biogen Exhibit 2138
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 30
`
`

`

`* Sections or subsections omitted from the full prescribing information are
`
`not listed.
`
`
`
`
`
`
`
`Reference ID: 4340211
`
`Page 2 of 30
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`GILENYA is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in patients 10 years of age and
`older.
`DOSAGE AND ADMINISTRATION
`2
`Assessment Prior to Initiating GILENYA
`2.1
`Cardiac Evaluation
`Obtain a cardiac evaluation in patients with certain preexisting conditions [see Warnings and Precautions (5.1)].
`Prior to starting treatment, determine whether patients are taking drugs that could slow heart rate or atrioventricular
`conduction [see Dosage and Administration (2.4) and Drug Interactions (7.5)].
`Complete Blood Count (CBC)
`Review results of a recent CBC [see Warnings and Precautions (5.2) and Drug Interactions (7.6)].
`Prior Medications
`If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior
`use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with
`GILENYA [see Warnings and Precautions (5.2) and Drug Interactions (7.4)].
`Vaccinations
`Test patients for antibodies to varicella zoster virus (VZV) before initiating GILENYA; VZV vaccination of antibody-
`negative patients is recommended prior to commencing treatment with GILENYA [see Warnings and Precautions (5.2)].
`It is recommended that pediatric patients if possible, complete all immunizations in accordance with current immunization
`guidelines prior to initiating GILENYA therapy.
`2.2
`Important Administration Instructions
`Patients who initiate GILENYA and those who reinitiate treatment after discontinuation for longer than 14 days require
`first-dose monitoring. This monitoring is also recommended when the dose is increased in pediatric patients [see Dosage
`and Administration (2.4, 2.5)].
`
`GILENYA can be taken with or without food.
`2.3
`Recommended Dosage
`In adults and pediatric patients 10 years of age and older weighing more than 40 kg, the recommended dosage of
`GILENYA is 0.5 mg orally once-daily.
`
`In pediatric patients 10 years of age and older weighing less than or equal to 40 kg, the recommended dosage of
`GILENYA is 0.25 mg orally once daily.
`
`Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional
`benefit.
`
`First-Dose Monitoring
`2.4
`Initiation of GILENYA treatment results in a decrease in heart rate, for which monitoring is recommended [see Warnings
`and Precautions (5.1) and Clinical Pharmacology (12.2)]. Prior to dosing and at the end of the observation period, obtain
`an electrocardiogram (ECG) in all patients.
`
`
`
`Reference ID: 4340211
`
`Page 3 of 30
`
`

`

`•
`•
`
`•
`
`
`First 6-Hour Monitoring
`Administer the first dose of GILENYA in a setting in which resources to appropriately manage symptomatic bradycardia
`are available. Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse
`and blood pressure measurement.
`Additional Monitoring after 6-Hour Monitoring
`Continue monitoring until the abnormality resolves if any of the following are present (even in the absence of symptoms)
`after 6 hours:
`• The heart rate 6 hours postdose is less than 45 bpm in adults, less than 55 bpm in pediatric patients 12 years of
`age and older, or less than 60 bpm in pediatric patients 10 or 11 years of age
`• 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.
`If postdose symptomatic bradycardia occurs, initiate appropriate management, begin continuous ECG monitoring, and
`continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological
`treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
`Overnight Monitoring
`Continuous overnight ECG monitoring in a medical facility should be instituted:
`in patients that require pharmacologic intervention for symptomatic bradycardia. In these patients, the first dose
`•
`monitoring strategy should be repeated after the second dose of GILENYA
`in patients with some preexisting heart and cerebrovascular conditions [see Warnings and Precautions (5.1)]
`in patients with a prolonged QTc interval before dosing or during 6-hour observation, or at additional risk for QT
`prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes [see
`Warnings and Precautions (5.1), Drug Interactions (7.1)]
`in patients receiving concurrent therapy with drugs that slow heart rate or atrioventricular conduction [see Drug
`Interactions (7.5)].
`2.5 Monitoring After Reinitiation of Therapy Following Discontinuation
`When restarting GILENYA after discontinuation for more than 14 days after the first month of treatment, perform
`first- dose monitoring, because effects on heart rate and AV conduction may recur on reintroduction of GILENYA
`treatment [see Dosage and Administration (2.4)]. The same precautions (first-dose monitoring) as for initial dosing are
`applicable. 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:
`• 0.25 mg hard capsules with an ivory opaque body and cap, with black radial imprint “FTY 0.25mg” on the cap
`and a black radial band on the capsule body.
`• 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.
`CONTRAINDICATIONS
`4
`GILENYA is contraindicated in patients who have:
`in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure
`•
`requiring hospitalization or Class III/IV heart failure
`a 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 [see Warnings and Precautions (5.1)]
`a baseline QTc interval ≥ 500 msec
`
`•
`
`•
`
`
`
`Reference ID: 4340211
`
`Page 4 of 30
`
`

`

`
`
`• concomitant treatment with Class Ia or Class III anti-arrhythmic drugs
`• 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 (5.13)].
`WARNINGS AND PRECAUTIONS
`5
`Bradyarrhythmia and Atrioventricular Blocks
`5.1
`Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA
`treatment initiation [see Dosage and Administration (2.4)].
`Reduction in Heart Rate
`After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart
`rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours postdose. Because of
`physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some
`patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours.
`Heart rates below 40 beats per minute in adults, and below 50 beats per minute in pediatric patients occurred rarely. In
`controlled clinical trials in adult patients, adverse reactions of symptomatic bradycardia following the first dose were
`reported in 0.6% of patients receiving GILENYA 0.5 mg and in 0.1% of patients on placebo. Patients who experienced
`bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations,
`and/or chest pain that usually resolved within the first 24 hours on treatment.
`Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart
`failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia,
`history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the
`GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to
`treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct
`such evaluation, and, if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility
`after the first dose.
`Since initiation of GILENYA treatment, results in decreased heart rate and may prolong the QT interval, patients with a
`prolonged QTc interval (> 450 msec adult and pediatric males, > 470 msec adult females, or > 460 msec pediatric
`females) before dosing or during 6 hour observation, or at additional risk for QT prolongation (e.g., hypokalemia,
`hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk
`of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored
`overnight with continuous ECG in a medical facility
`Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second
`dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the
`heart rate returns to baseline within 1 month of chronic treatment. Clinical data indicate effects of GILENYA on heart rate
`are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after
`initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient
`reports of cardiac symptoms.
`Atrioventricular Blocks
`Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials in adult
`patients, first-degree AV block after the first dose occurred in 4.7% of patients receiving GILENYA and 1.6% of patients
`on placebo. In a study of 697 patients with available 24-hour Holter monitoring data after their first dose (N = 351
`receiving GILENYA and N = 346 on placebo), second-degree AV blocks (Mobitz Types I [Wenckebach] or 2:1 AV
`blocks) occurred in 4% (N = 14) of patients receiving GILENYA and 2% (N = 7) of patients on placebo. Of the 14
`patients receiving GILENYA, 7 patients had 2:1 AV block (5 patients within the first 6 hours postdose and 2 patients after
`6 hours postdose). All second degree AV blocks on placebo were Mobitz Type I and occurred after the first 12 hours
`postdose. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours
`on treatment, but they occasionally required treatment with atropine or isoproterenol.
`
`
`
`Reference ID: 4340211
`
`Page 5 of 30
`
`

`

`
`Postmarketing Experience
`In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the
`first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and
`unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant
`medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also
`reported after the first dose of GILENYA.
`5.2
`Infections
`Risk of Infections
`GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of
`reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections,
`some serious in nature [see Clinical Pharmacology (12.2)]. Life-threatening and fatal infections have occurred in
`association with GILENYA.
`Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy)
`should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess
`the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take
`up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report
`symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the
`infection(s) is resolved.
`In MS placebo-controlled trials in adult patients, the overall rate of infections (72%) with GILENYA was similar to
`placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in GILENYA-
`treated patients. Serious infections occurred at a rate of 2.3% in the GILENYA group versus 1.6% in the placebo group.
`In the postmarketing setting, serious infections with opportunistic pathogens including viruses (e.g., John Cunningham
`virus (JCV), herpes simplex viruses 1 and 2, varicella-zoster virus), fungi (e.g., cryptococci), and bacteria (e.g., atypical
`mycobacteria) have been reported with GILENYA. Patients with symptoms and signs consistent with any of these
`infections should undergo prompt diagnostic evaluation and appropriate treatment.
`Herpes Viral Infections
`In placebo-controlled trials in adult patients, the rate of herpetic infections was 9% in patients receiving GILENYA 0.5
`mg and 7% on placebo.
`Two patients died of herpetic infections during controlled trials. One death was due to disseminated primary herpes zoster
`and the other was to herpes simplex encephalitis. In both cases, the patients were taking a 1.25 mg dose of fingolimod
`(higher than the recommended 0.5 mg dose) and had received high-dose corticosteroid therapy to treat suspected MS
`relapses.
`Serious, life-threatening events of disseminated varicella zoster and herpes simplex infections, including cases of
`encephalitis and multiorgan failure, have occurred with GILENYA in the postmarketing setting. Include disseminated
`herpetic infections in the differential diagnosis of patients who are receiving GILENYA and present with an atypical MS
`relapse or multiorgan failure.
`Cases of Kaposi’s sarcoma have been reported in the postmarketing setting. Kaposi’s sarcoma is an angioproliferative
`disorder that is associated with infection with human herpes virus 8 (HHV-8). Patients with symptoms or signs consistent
`with Kaposi’s sarcoma should be referred for prompt diagnostic evaluation and management.
`Cryptococcal Infections
`Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, have
`been reported with GILENYA in the postmarketing setting. Cryptococcal infections have generally occurred after
`approximately 2 years of GILENYA treatment, but may occur earlier. The relationship between the risk of cryptococcal
`infection and the duration of treatment is unknown. Patients with symptoms and signs consistent with a cryptococcal
`infection should undergo prompt diagnostic evaluation and treatment.
`
`
`
`Reference ID: 4340211
`
`Page 6 of 30
`
`

`

`
`Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies
`In clinical studies, patients who received GILENYA did not receive concomitant treatment with antineoplastic, non-
`corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of
`GILENYA with any of these therapies, and also with corticosteroids, would be expected to increase the risk of
`immunosuppression [see Drug Interactions (7.4)].
`When switching to GILENYA from immune-modulating or immunosuppressive medications, consider the duration of
`their effects and their mode of action to avoid unintended additive immunosuppressive effects.
`Varicella Zoster Virus Antibody Testing/Vaccination
`Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of
`vaccination against 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 [see Drug Interactions (7.3) and Use in Specific Populations (8.4)].
`5.3
`Progressive Multifocal Leukoencephalopathy
`Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS who received GILENYA
`in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that
`typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML
`has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML,
`were not taking any other immunosuppressive or immunomodulatory medications concomitantly, and did not have any
`ongoing systemic medical conditions resulting in compromised immune system function. The majority of 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.
`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.
`MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and
`the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have
`been reported in patients treated with MS medications associated with PML, including GILENYA. Many of these patients
`subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML
`may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if
`present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS
`medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML
`who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early
`detection and discontinuation of MS treatment or due to differences in disease in these patients.
`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 to 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 adult patients with multiple sclerosis, macular edema with or
`without visual symptoms occurred in 1.5% of patients (11/799) treated with fingolimod 1.25 mg, 0.5% of patients (4/783)
`treated with GILENYA 0.5 mg and 0.4% of patients (3/773) treated with placebo. Macular edema occurred predominantly
`during the first 3 to 4 months of therapy. These clinical trials excluded patients with diabetes mellitus, a known risk factor
`for macular edema (see below Macular Edema in Patients with History of Uveitis or Diabetes Mellitus). Symptoms of
`macular edema included blurred vision and decreased visual acuity. Routine ophthalmological examination detected
`macular edema in some patients with no visual symptoms. Macular edema generally partially or completely resolved with
`or without treatment after drug discontinuation. Some patients had residual visual acuity loss even after resolution of
`
`
`
`Reference ID: 4340211
`
`Page 7 of 30
`
`

`

`
`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.
`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 in adult patients 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 adult patients receiving
`GILENYA. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and
`seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in
`diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be
`discontinued.
`5.6
`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 in adult patients, the reduction from baseline in the percent of predicted values for FEV1 at
`the time of last assessment on drug was 2.8% for GILENYA 0.5 mg and 1.0% for placebo. For DLCO, the reduction from
`baseline in percent of predicted values at the time of last assessment on drug was 3.3% for GILENYA 0.5 mg and 0.5%
`for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient
`information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS placebo-controlled
`trials in adult patients, dyspnea was reported in 9% of patients receiving GILENYA 0.5 mg and 7% of patients receiving
`placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled)
`studies. GILENYA has not been tested in MS patients with compromised respiratory function.
`Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with
`GILENYA if clinically indicated.
`5.7
`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 in adult patients, 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.
`
`
`
`Reference ID: 4340211
`
`Page 8 of 30
`
`

`

`
`Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely
`monitored, as the risk of adverse reactions is greater [see Use in Specific Populations (8.6), Clinical Pharmacology
`(12.3)].
`5.8
`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 effe