Data from FDA - Curated by EPG Health - Last updated 12 July 2018

Indication(s)

1 INDICATIONS AND USAGE GILENYA is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in patients 10 years of age and older. 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)

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Advisory information

contraindications
4 CONTRAINDICATIONS 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 AV block or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.1)] a baseline QTc interval ≥ 500 msec 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 (5.12)]. 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. Adults 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 in clinical studies in adults that occurred in ≥ 1% of GILENYA-treated patients and ≥ 1% higher rate than for placebo. Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥ 1% of Patients and Reported for GILENYA 0.5 mg at ≥ 1% Higher Rate than for Placebo) Adverse Drug Reactions 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 seizure, 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. Seizure Cases of seizures have been reported with the use of GILENYA in clinical trials and in the postmarketing setting in adults. In adult clinical trials, the rate of seizures was 0.9% in GILENYA-treated patients and 0.3% in placebo-treated patients. It is unknown whether these events were related to the effects of multiple sclerosis alone, to GILENYA, or to a combination of both. Pediatric Patients 10 Years of Age and Older In the controlled pediatric trial (Study 4), the safety profile in pediatric patients receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. In the pediatric study, cases of seizures were reported in 5.6% of GILENYA-treated patients and 0.9% of interferon beta-1a-treated patients [see Use in Specific Populations (8.4)].

Usage information

Dosing and administration
2 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 dosge 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 reinitiation after discontinuation > 14 days and dose increases): 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) Monitor until resolution if heart rate < 45 beats per minute (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) Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. (2.4) 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) 2.1 Assessment Prior to Initiating GILENYA 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 (AV) conduction [see Dosage and Administration (2.4), Drug Interactions (7.5)]. Complete Blood Count (CBC) Review results of a recent CBC [see Warnings and Precautions (5.2), 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), 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. 2.4 First-Dose Monitoring Initiation of GILENYA treatment results in a decrease in heart rate, for which monitoring is recommended [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2)]. Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients. 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 is 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 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 cerebrocascular 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 AV 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 (2.0)]. 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to GILENYA during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the GILENYA pregnancy registry by calling 1-877-598-7237, sending an email to [email protected], or visiting www.gilenyapregnancyregistry.com. Risk Summary There are no adequate data on the developmental risk associated with the use of GILENYA in pregnant women. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including an increase in malformations (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose of 0.5 mg/day on a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats were 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. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data 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 recommended human dose (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 Lactation Risk Summary There are no data on the presence of fingolimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Fingolimod is excreted in the milk of treated rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clincial need for GILENYA and any potential adverse effects on the breastfed infant from GILENYA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Before initiation of GILENYA treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with GILENYA [see Use in Specific Populations (8.1)]. Since it takes approximately 2 months to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period [see Warnings and Precautions (5.8, 5.11)]. 8.4 Pediatric Use Safety and effectiveness of GILENYA for the treatment of relapsing forms of multiple sclerosis in pediatric patients 10 to less than 18 years of age were established in one randomized, double-blind clinical study in 215 patients (GILENYA n = 107; intramuscular interferon (IFN) beta-1a n = 108) [see Clinical Studies (14.2)]. In the controlled pediatric study, the safety profile in pediatric patients (10 to less than 18 years of age) receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. In the pediatric study, cases of seizures were reported in 5.6% of GILENYA treated patients and 0.9% of interferon beta-1a treated patients. It is recommended that pediatric patients if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating GILENYA therapy. Safety and effectiveness of GILENYA in pediatric patients below the age of 10 years have not been established. Juvenile Animal Toxicity Data 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. Overall, a no-effect dose for adverse developmental effects in juvenile animals was not identified. 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), 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.

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 (2.4), 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. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating GILENYA therapy. 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 AV 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 physician prescribing these drugs 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 (2.4), 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 0078-0965,0078-0607
Date Last Revised 11-05-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.2 Storage and Handling GILENYA capsules should be stored at 25ºC (77ºF); excursions permitted to 15ºC–30ºC (59ºF–86ºF). Protect from moisture.
Marketing authorisation holder Novartis Pharmaceuticals Corporation