---------------WARNINGS AND PRECAUTIONS------------
`• Decrease in heart rate and/or atrioventricular conduction after first dose
`
`of GILENYA: Monitor patients (2, 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)
`
`• 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 starting GILENYA.
`
`Assess liver enzymes if hepatic injury is suspected. Discontinue
`GILENYA if significant liver injury occurs (5.5)
`• Fetal risk: Women of childbearing potential should use effective
`
`contraception during and for 2 months after stopping GILENYA (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
`FDA-1088 or www.fda.gov/medwatch.
`-------------------DRUG INTERACTIONS--------------------­
`
`• Ketoconazole: Monitor patients closely, as GILENYA exposure is
`
`
`increased by 70% 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 not 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, 8.6, 12.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide
`
`
`
`
`
`
`
` 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
`
`
`
`
`--------------RECENT MAJOR CHANGES--------------------­
`
`
`
`Dosage and Administration (2)
`
`
`
`04/2012
`
`
`Contraindications (4)
`04/2012
`
`
`
`
`
`
`Warnings and Precautions (5.1, 5.7)
`04/2012
`
`
`
`--------------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)
`
`
`• First Dose Monitoring:
`
`
`o Observe all patients for signs and symptoms of bradycardia for at least 6 hours
`
`after first dose with hourly pulse and blood pressure measurement. Obtain
`
`
`ECG prior to dosing and at the end of the observation period.
`
`
`
`o Patients who develop a heart rate <45 bpm, or a new onset 2nd degree or
`
`higher atrioventricular block should be monitored until resolution of the
`finding. Patients at lowest post-dose heart rate at the end of the observation
`period should be monitored until heart rate increases.
`
`o In patients experiencing symptomatic bradycardia, begin continuous ECG
`monitoring until the symptoms have resolved; if pharmacological intervention
`is required to treat bradycardia, continuous ECG monitoring should continue
`overnight in a medical facility, and first-dose monitoring procedures should be
`repeated for the second dose.
`
`
`o Patients at higher risk of symptomatic bradycardia or heart block because of a
`coexisting medical condition or certain concomitant medications should be
`observed overnight with continuous ECG monitoring (2).
`
`
`o Patients with prolonged QTc interval at baseline or during the observation
`period, or taking drugs with known risk of torsades de pointes should be
`observed overnight with continuous ECG monitoring (2).
`
`-----------DOSAGE FORMS AND STRENGTHS-----------­
`0.5 mg hard capsules. (3)
`
`---------------------CONTRAINDICATIONS------------------­
`
`• Recent (within the last 6 months) occurrence of: myocardial infarction, unstable
`
`angina, stroke, transient ischemic attack, decompensated heart failure requiring
`hospitalization, or Class III/IV heart failure (4)
`
`• History or presence 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 ms (4)
`
`
`
`• Treatment with Class Ia or Class III anti-arrhythmic drugs (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 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
`
`
`
`
`
`
`
`Reference ID: 3120045
`
`
`
`
`
`
`
`Revised: 05/2012
`
`
`
`
`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
`
`
`
`
`
`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
`
`Page 1 of 17
`
`Coalition Exhibit 1065
`Coalition v. Biogen
`IPR2015-01993
`
`

`
`
`
`
` 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.
`
`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 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 post-dose is <45 bpm
`• The heart rate 6 hours post-dose is at the lowest value post-dose (suggesting that the maximum pharmacodynamic
`effect on the heart may not have occurred)
`• The ECG 6-hours post-dose shows new onset second degree or higher AV block
`Should post-dose 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 pre-existing conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart
`
`failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope,
`severe untreated sleep apnea, AV block, sino-atrial 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,
`concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block.
`
`
`
`
`Reference ID: 3120045
`
`Page 2 of 17
`
`

`
`
`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. In patients who cannot switch, overnight continuous ECG
`
`monitoring after the first dose is recommended [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, 2-4 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.
`Re-initiation 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 one day or more, during week 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 two 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 ms
`
`
`Treatment with Class Ia or Class III anti-arrhythmic drugs
`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 maximal decline in heart
`rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8-10 hours post dose. 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. Adverse reactions of symptomatic 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 hypotension, dizziness, fatigue,
`
`palpitations, and 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 one month of chronic treatment.
`Atrioventricular blocks
`
`Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse
`reactions of first-degree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of
`patients receiving GILENYA 0.5 mg, but in no patient on placebo. Second-degree AV blocks following the first dose
`were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698
`
`patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5 mg and N=347 on
`placebo), second-degree AV blocks, Mobitz types I (Wenckebach) and/or II, were reported in 3.7% (N=13) of patients
`
`
`Reference ID: 3120045
`
`Page 3 of 17
`
`

`
`
`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.
`
`Post-marketing experience
`In the post-marketing setting, third degree AV block and AV block with junctional escape have been observed during the
`first-dose six-hour observation period 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 pre-existing 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) 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.
`
`
`
`Reference ID: 3120045
`
`Page 4 of 17
`
`

`
`
`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 6-9 months. Serum transaminase
`levels returned to normal within approximately 2 months after discontinuation of GILENYA.
`
`Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as
`unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. GILENYA should be
`
`discontinued if significant liver injury is confirmed. Patients with pre-existing liver disease may be at increased risk of
`
`developing elevated liver enzymes when taking GILENYA.
`
`Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely
`monitored, as the risk of adverse reactions is greater [see Use in Specific Populations (8.6) 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 1 month 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
`
`
`Reference ID: 3120045
`
`Page 5 of 17
`
`

`
`
`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)
`
`
`GILENYA 0.5 mg
`N=425
`%
`
`
`
`13
`9
`8
`7
`5
`4
`
`4
`
`
`25
`7
`5
`5
`
`
`12
`
`
`Placebo
`N=418
`%
`
`
`
`10
`8
`4
`5
`3
`1
`
`1
`
`23
`6
`4
`1
`
`7
`
`
`
`
`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
`
`
`
`
`
`Reference ID: 3120045
`
`Page 6 of 17
`
`

`
`
`
`Primary System Organ Class
`Preferred Term
`
`
`
`
`Asthenia
`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
`
`GILENYA 0.5 mg
`N=425
`%
`
`3
`
`
`
`12
`
`4
`3
`3
`
`
`14
`5
`5
`3
`
`
`Placebo
`N=418
`%
`
`1
`
`
`7
`
`2
`2
`1
`
`5
`1
`3
`1
`
`
`
`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
`
`QT prolonging drugs
`GILENYA has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT
`
`interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of GILENYA
`treatment results in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs with a known
`
`risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored
`
`
`
`Reference ID: 3120045
`
`Page 7 of 17
`
`

`
`
`overnight with continuous ECG in a medical facility [see Dosage and Administration (2) and Warnings and Precautions
`
`
`
`(5.1)].
`
`Ketoconazole
`The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly 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.
`
`
`Drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers or diltiazem)
`Experience with GILENYA in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular
`conduction (e.g., beta blockers, digoxin, or heart-rate slowing calcium channel blockers such as diltiazem or verapamil) is
`limited. Because initiation of GILENYA treatment may result in an additional decrease in heart rate, concomitant use of
`these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. Seek advice from the
`prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular
`conduction before initiating GILENYA. In patients who cannot switch, consider extended monitoring, including overnight,
`
`after the first dose [see Dosage and Administration (2) and Warnings and Precautions (5.1)].
`
`
`
`
`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 l