Data from FDA - Curated by EPG Health - Last updated 07 May 2018

Indication(s)

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. 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)

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contraindications
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)]. 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)
Adverse reactions
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)] Cutaneous Malignancies [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)] 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. 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 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 occurred in ≥ 1% of GILENYA-treated patients and ≥ 1% higher rate than for placebo. Table 1 Adverse Reactions Reported in Studies 1 and 3 (Occurring in ≥1% of Patients and Reported for GILENYA 0.5 mg at ≥1% Higher Rate than for Placebo) Primary System Organ Class Preferred Term GILENYA 0.5 mg N=783 % Placebo N=773 % Infections Influenza 11 8 Sinusitis 11 8 Bronchitis 8 5 Herpes zoster 2 1 Tinea versicolor 2 <1 Cardiac Disorders Bradycardia 3 1 Nervous system disorders Headache 25 24 Migraine 6 4 Gastrointestinal disorders Nausea 13 12 Diarrhea 13 10 Abdominal pain 11 10 General disorders and administration site conditions Asthenia 2 1 Musculoskeletal and connective tissue disorders Back pain 10 9 Pain in extremity 10 7 Skin and subcutaneous tissue disorders Alopecia 3 2 Actinic keratosis 2 1 Investigations Liver transaminase elevations (ALT/GGT/AST) 15 4 Blood triglycerides increased 3 1 Respiratory, thoracic, and mediastinal disorders Cough 12 11 Dyspnea 9 7 Eye disorders Vision blurred 4 2 Vascular disorders Hypertension 8 4 Blood and lymphatic system disorders Lymphopenia 7 <1 Leukopenia 2 <1 Neoplasms benign, malignant and unspecified (including cysts and polyps) Skin papilloma 3 2 Basal cell carcinoma 2 1 Adverse reactions of dizziness, pneumonia, eczema and pruritus were also reported in Studies 1 and 3 but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%). Adverse reactions with GILENYA 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3. Vascular Events Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25-5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA in the postmarketing setting although a causal relationship has not been established. Lymphoma Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving GILENYA. The reporting rate of non-Hodgkin lymphoma with GILENYA is greater than that expected in the general population adjusted by age, gender, and region. The relationship of lymphoma to GILENYA remains uncertain.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dose: 0.5 mg orally once-daily, with or without food (2.1) First Dose Monitoring (including re-initiation after discontinuation >14 days): 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. (2.2) 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. (2.2) Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. (2.2) 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. (2.2, 7.1) 2.1 Recommended Dosage The recommended dosage 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 Dosage and Administration (2.2, 2.3)]. 2.2 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 (7.1)]. 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. 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 (7.1)]. 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. 2.3 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including teratogenicity (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats included persistent truncus arteriosus and ventricular septal defect. The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. Because it takes approximately 2 months to eliminate fingolimod from the body, potential risks to the fetus may persist after treatment ends [see Warnings and Precautions (5.8, 5.11)]. GILENYA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Registry A pregnancy registry has been established to collect information about the effect of GILENYA use during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the GILENYA pregnancy registry by calling Quintiles at 1-877-598-7237, sending an email to [email protected] or visiting www.gilenyapregnancyregistry.com. Animal Data When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryo-fetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the RHD on a mg/m2 basis. Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryo-fetal mortality and fetal growth retardation at the mid and high doses. The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m2 basis. When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m2 basis. 8.2 Labor and Delivery The effects of GILENYA on labor and delivery are unknown. 8.3 Nursing Mothers Fingolimod is excreted in the milk of treated rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GILENYA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of GILENYA in pediatric patients with MS below the age of 18 years have not been established. In a study in which fingolimod (0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, changes in bone mineral density and persistent neurobehavioral impairment (altered auditory startle) were observed at all doses. Delayed sexual maturation was noted in females at the highest dose tested and in males at all doses. The bone changes observed in fingolimod-treated juvenile rats are consistent with a reported role of S1P in the regulation of bone mineral homeostasis. When fingolimod (0.5 or 5 mg/kg/day) was orally administered to rats from the neonatal period through sexual maturity, a marked decrease in T-cell dependent antibody response was observed at both doses. This effect had not fully recovered by 6-8 weeks after the end of treatment. 8.5 Geriatric Use Clinical MS studies of GILENYA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. GILENYA should be used with caution in patients aged 65 years and over, reflecting the greater frequency of decreased hepatic, or renal, function and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Because fingolimod, but not fingolimod-phosphate, exposure is doubled in patients with severe hepatic impairment, patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions may be greater [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. No dose adjustment is needed in patients with mild or moderate hepatic impairment. 8.7 Renal Impairment The blood level of some GILENYA metabolites is increased (up to 13-fold) in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. The toxicity of these metabolites has not been fully explored. The blood level of these metabolites has not been assessed in patients with mild or moderate renal impairment.
Pregnancy and lactation
8.3 Nursing Mothers Fingolimod is excreted in the milk of treated rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GILENYA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 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) 7.1 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 overnight with continuous ECG in a medical facility [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 7.2 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. 7.3 Vaccines GILENYA reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA [see Clinical Pharmacology (12.2)]. Avoid the use of live attenuated vaccines during and for 2 months after treatment with GILENYA because of the risk of infection. 7.4 Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with GILENYA. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating GILENYA [see Warnings and Precautions (5.2)]. 7.5 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. Patients who cannot switch, should have overnight continuous ECG monitoring after the first dose [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 7.6 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.

More information

Category Value
Authorisation number NDA022527
Agency product number G926EC510T
Orphan designation No
Product NDC 0078-0607
Date Last Revised 15-12-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Novartis Pharmaceuticals Corporation