Gilenya

— THERAPEUTIC DISORDERS TREATED —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Gilenya Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Fingolimod (as HCl) 0.25mg, 0.5mg; hard gel caps.

    Pharmacological Class

    Sphingosine 1-phosphate receptor modulator.

    How Supplied

    Caps—30; Blister cards—7

    How Supplied

    0.25 mg Gilenya capsules are supplied as follows: 

    • hard gelatin capsules with an ivory opaque body and cap, with black radial imprint “FTY 0.25 mg” on the cap and a black radial band on the capsule body

    • Bottle of 30 capsules 

    • Carton of 7 capsules containing 1 blister card of 7 capsules per blister card

    0.5 mg Gilenya capsules are supplied as follows:

    • hard gelatin 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

    • Bottle of 30 capsules

    • Carton of 7 capsules containing 1 blister card of 7 capsules per blister card

    Storage

    Gilenya capsules should be stored at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Protect from moisture.

    Manufacturer

    Novartis Pharmaceuticals Corp

    Generic Availability

    NO

    Gilenya Indications

    Indications

    Relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

    Gilenya Dosage and Administration

    Prior to Treatment Evaluations

    Cardiac Evaluation 

    • Obtain a cardiac evaluation in patients with certain preexisting conditions. Prior to initiation, determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction. 

    Complete Blood Count (CBC)

    • Obtain a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) before initiating treatment with Gilenya.

    Serum transaminases (ALT and AST) and Total Bilirubin Levels

    • Prior to initiation (i.e., within 6 months), obtain serum transaminases (ALT and AST) and total bilirubin levels.

    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.

    Vaccinations

    • Test patients for antibodies to varicella zoster virus (VZV) before initiating; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with Gilenya. It is recommended that pediatric patients if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating Gilenya therapy.

    Adults and Children

    <10yrs: not established. ≥10yrs (>40kg): 0.5mg once daily; (≤40kg): 0.25mg once daily. First dose monitoring for bradycardia: see Warnings/Precautions. Re-initiation of therapy after discontinuation for >14 days: within first 2 weeks, first dose procedures are recommended after interruption of 1 day or more; during week 3 and 4, first dose procedures are recommended after interruption of more than 7 days. Children: observe first dose monitoring when dose increased.

    Adults and Children

    Recommended Dosage

    • In adults and pediatric patients 10 years of age and older weighing more than 40 kg: 0.5 mg orally once-daily. 

    • In pediatric patients 10 years of age and older weighing less than or equal to 40 kg: 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.

    • 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.

    First-Dose Monitoring

    • Initiation of Gilenya treatment results in a decrease in heart rate, for which monitoring is recommended. 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 post-dose is less than 45 beats per minute (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 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 atrioventricular (AV) block. 

    • If post-dose 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; 

      • 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; 

      • in patients receiving concurrent therapy with drugs that slow heart rate or AV conduction.

    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. 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.

    Renal Impairment

    The blood level of some Gilenya metabolites is increased (up to 13-fold) in patients with severe renal impairment. 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.

    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.

    No dose adjustment is needed in patients with mild or moderate hepatic impairment.  

    Other Modifications

    Females and Males of Reproductive Potential

    • Pregnancy Testing: The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Gilenya. 

    • Contraception: Counsel patients on the potential for a serious risk to the fetus and the need for effective contraception during treatment with Gilenya before initiation. 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.

    Gilenya Contraindications

    Contraindications

    Recent (within the last 6 months) occurrence of: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, Class III/IV heart failure. History or presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless paced. Baseline QTc interval ≥500ms. Arrhythmias requiring treatment with Class Ia or Class III antiarrhythmic drugs.

    Gilenya Boxed Warnings

    Not Applicable

    Gilenya Warnings/Precautions

    Warnings/Precautions

    Risk of bradyarrhythmia; observe all patients for bradycardia for at least 6hrs after first dose with hourly pulse and BP measurement. Obtain ECG prior to dosing and at the end of observation period. If heart rate (HR) <45bpm (adults), <55bpm (≥12yrs) or <60bpm (10–11yrs), or new onset 2nd degree or higher AV block; monitor until resolution, those at the lowest post-dose HR should be monitored until HR increases. Symptomatic bradycardia: begin continuous ECG monitoring until resolved; if pharmacological intervention necessary, continue ECG monitoring overnight, and first dose monitoring procedures should be repeated for 2nd dose. Pre-existing cardiac conditions (eg, ischemic heart disease, history of MI, cardiac arrest or symptomatic bradycardia, cerebrovascular disease, CHF, uncontrolled hypertension, recurrent syncope, untreated sleep apnea, AV block, sino-atrial block), QT prolongation risk (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome): monitor ECG overnight after first dose. Monitor BP during treatment. Increased risk of infections (may be fatal). Obtain recent CBC before starting treatment. Consider suspending therapy if serious infection develops; continue monitoring for 2 months after discontinuation. Active acute or chronic infection: do not start treatment until infection resolved. Test for antibodies to varicella zoster virus; consider immunization before starting fingolimod. Consider HPV immunization prior to initiation. Perform cancer screening (including Pap test). Immunosuppressed. Withhold and evaluate at first sign/symptom of progressive multifocal leukoencephalopathy (PML). Diabetes, history of uveitis: increased risk of macular edema. Monitor visual acuity and for visual disturbances. Do ophthalmic exam at baseline, and at 3–4 months after starting therapy. Renal or severe hepatic impairment. Obtain ALT, AST, total bilirubin prior to initiation (eg, within 6 months); monitor periodically until 2 months after stopping treatment. Monitor for hepatic injury; discontinue if occurs. Interrupt treatment if ALT >3 times the reference range with total bilirubin >2 times the reference range; do not resume if no alternative etiology established. Respiratory dysfunction; obtain spirometry and DLCO when needed. Monitor for severe increase in disability after treatment discontinuation. Malignancies. Consider tumefactive MS if severe MS relapse occurs during (esp initiation) or after discontinuing. Perform periodic skin exam (esp. with risk factors); monitor for suspicious skin lesions and evaluate if observed. Complete all immunizations in children prior to initiation. Elderly. Advise females of reproductive potential to use effective contraception during and for 2 months after discontinuation. Pregnancy: exclude status prior to initiation. Nursing mothers.

    Warnings/Precautions

    Bradyarrhythmia and Atrioventricular Blocks

    • Reduction in Heart Rate 

      • Monitor during treatment initiation due to the risk for bradyarrhythmia and AV blocks.

      • The following patients may poorly tolerate the Gilenya-induced bradycardia, or experience serious rhythm disturbances after the first dose of Gilenya: patients with some preexisting conditions (e.g., ischemic heart disease, history of MI, CHF, 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). 

      • Perform cardiac evaluation prior to treatment, and if treated with Gilenya, monitor overnight with continuous ECG in a medical facility after the first dose.

      • Monitor the following patients overnight with continuous ECG in a medical facility: 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; 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).

    • Atrioventricular Blocks 

      • Initiation of Gilenya treatment has resulted in transient AV conduction delays. 

      • 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.

    Infections

    • Obtain a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) before initiating treatment with Gilenya. 

    • Consider suspending treatment with Gilenya if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. 

    • Continue monitoring for infections throughout this period because the elimination of fingolimod after discontinuation may take up to 2 months. 

    • Do not initiate treatment in patients with active acute or chronic infections until the infection(s) is resolved.

    • Perform prompt diagnostic evaluation and appropriate treatment in patients with symptoms and signs consistent with any of the following infections: 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).

    • Herpes Viral Infections: 

      • Perform prompt diagnostic evaluation and management in patients with symptoms or signs consistent with Kaposi’s sarcoma.

    • Cryptococcal Infections: 

      • Perform prompt diagnostic evaluation and treatment in patients with symptoms or signs consistent with a cryptococcal infection.

    • Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies: 

      • Consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects when switching to Gilenya from immune-modulating or immunosuppressive medications.

    • Varicella Zoster Virus Antibody Testing/Vaccination: 

      • Test for antibodies to VZV before initiating Gilenya in patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV. 

      • 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.

    • Human Papilloma Virus (HPV) Infection: 

      • Consider HPV vaccination prior to treatment initiation.

      • Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.

    Progressive Multifocal Leukoencephalopathy (PML)

    • Withhold Gilenya and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML.

    • MRI findings may be apparent before clinical signs or symptoms. 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.

    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.  

    • Assess potential benefits and risks on whether or not to discontinue Gilenya therapy. The risk of recurrence after rechallenge has not been evaluated.

    • Increased risk of macular edema during Gilenya therapy in patients with a history of uveitis and patients with diabetes mellitus. MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations prior to treatment and at 3 to 4 months after starting treatment.

    Liver Injury

    • Obtain serum transaminases (ALT and AST) and total bilirubin levels prior to starting treatment with Gilenya (within 6 months). Obtain transaminase levels and total bilirubin levels periodically until two months after Gilenya discontinuation.

    • Monitor for signs and symptoms of any hepatic injury. Measure liver transaminase and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 

    • Do not be resume treatment if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury.

    • Monitor closely in patients with severe hepatic impairment because Gilenya exposure is doubled.

    Posterior Reversible Encephalopathy Syndrome (PRES)

    • 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. 

    • Discontinue treatment If PRES is suspected.

    Respiratory Effects

    • Gilenya has not been tested in MS patients with compromised respiratory function. 

    • Perform spirometric evaluation of respiratory function and evaluation of diffusion lung capacity for carbon monoxide (DLCO) during therapy if clinically indicated.

    Fetal Risk

    • Based on findings from animal studies, Gilenya may cause fetal harm when administered to a pregnant woman. 

    • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping Gilenya treatment.

    Severe Increase in Disability After Stopping Gilenya 

    • Monitor for development of severe increase in disability following discontinuation of Gilenya and begin appropriate treatment as needed.

    Tumefactive Multiple Sclerosis

    • Tumefactive MS should be considered when a severe MS relapse occurs during Gilenya treatment, especially during initiation, or after discontinuation of Gilenya, prompting imaging evaluation and initiation of appropriate treatment.

    Increased Blood Pressure

    • Monitor blood pressure (BP) during treatment with Gilenya.

    Malignancies

    • Cutaneous Malignancies  

      • Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. 

      • Monitor for suspicious skin lesions. Promptly evaluate if a suspicious skin lesion is observed. Limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor due to an increased risk for skin cancer.

    • Lymphoma 

      • Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving Gilenya. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported with Gilenya in the postmarketing setting.

    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. Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration.

    Hypersensitivity Reactions

    • Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported with Gilenya in the postmarketing setting. Gilenya is contraindicated in patients with history of hypersensitivity to fingolimod or any of its excipients.

    Pregnancy Considerations

    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 

    • Based on findings from animal studies, Gilenya may cause fetal harm when administered to a pregnant woman. Data from prospective reports to the Gilenya Pregnancy Registry (GPR) are currently not sufficient to allow for an adequate assessment of the drug-associated risk for birth defects and miscarriage in humans.

    Clinical Considerations 

    • In females planning to become pregnant, Gilenya should be stopped 2 months before planned conception. The possibility of severe increase in disability should be considered in women who discontinue or are considering discontinuation of Gilenya because of pregnancy or planned pregnancy.

    Nursing Mother Considerations

    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. 

    • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Gilenya and any potential adverse effects on the breastfed infant from Gilenya or from the underlying maternal condition.

    Pediatric Considerations

    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.

    Geriatric Considerations

    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.

    Renal Impairment Considerations

    The blood level of some Gilenya metabolites is increased (up to 13-fold) in patients with severe renal impairment. 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.

    Hepatic Impairment Considerations

    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.

    No dose adjustment is needed in patients with mild or moderate hepatic impairment.  

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Pregnancy Testing: The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Gilenya. 

    • Contraception: Counsel patients on the potential for a serious risk to the fetus and the need for effective contraception during treatment with Gilenya before initiation. 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.

    Gilenya Pharmacokinetics

    Absorption

    The Tmax of fingolimod is 12–16 hours. The apparent absolute oral bioavailability is 93%. Food intake does not alter Cmax or (AUC) of fingolimod or fingolimod-phosphate. Therefore, Gilenya may be taken without regard to meals. Steady-state blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

    Distribution

    Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of < 17%. Fingolimod and fingolimod-phosphate are > 99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment. Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200 ± 260 L. 

    Metabolism

    The biotransformation of fingolimod in humans occurs by 3 main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate, by oxidative biotransformation catalyzed mainly by the cytochrome P450 4F2 (CYP4F2) and possibly other CYP4F isoenzymes with subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod. Inhibitors or inducers of CYP4F2 and possibly other CYP4F isozymes might alter the exposure of fingolimod or fingolimod-phosphate. In vitro studies in hepatocytes indicated that CYP3A4 may contribute to fingolimod metabolism in the case of strong induction of CYP3A4.

    Elimination

    Fingolimod blood clearance is 6.3 ± 2.3 L/h, and the average apparent terminal half-life (t1/2) is 6 to 9 days. Blood levels of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, yielding similar half-lives for both. After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose.

    Gilenya Interactions

    Interactions

    Concomitant QT prolonging drugs (eg, citalopram, chlorpromazine, haloperidol, methadone, erythromycin): risk of torsades de pointes; monitor. Potentiated by ketoconazole; monitor if receiving systemic therapy. Concomitant β-blockers, digoxin, diltiazem, verapamil may be associated with severe bradycardia or heart block; consider alternatives. Avoid live virus vaccines during treatment and for 2 months after discontinuing fingolimod; may have suboptimal response. Antineoplastic, immunosuppressant or immunomodulating therapies may increase risk of immunosuppression; use caution when switching from long-acting immunotherapies (eg, natalizumab, teriflunomide, mitoxantrone).

    Gilenya Adverse Reactions

    Adverse Reactions

    Headache, increased liver transaminases, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, pain in extremity; bradyarrhythmia, AV blocks, hypertension, increased infection risk, macular edema, decreased pulmonary function, basal cell carcinoma/melanoma, lymphoma, hypersensitivity reactions; rare: posterior reversible encephalopathy syndrome (discontinue if suspected), PML.

    Gilenya Clinical Trials

    Clinical Trials

    Adults

    The efficacy of Gilenya was evaluated in 2 studies (Study 1 and 2) in patients with relapsing-remitting MS (RRMS) who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5.

    Study 1 was a 2-year randomized, double-blind, placebo-controlled study in patients with RRMS who had not received any interferon-beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening, Month 6, Month 12, and Month 24. 

    Patients were randomized to receive Gilenya 0.5 mg (N = 425), 1.25 mg (N = 429), or placebo (N = 418) for up to 24 months. The primary endpoint was the annualized relapse rate. The secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5) sustained for 3 months.

    Results from Study 1 showed that the annualized relapse rate was significantly lower in patients treated with Gilenya 0.5 mg than in patients who received placebo. The 1.25 mg dose resulted in no additional benefit over the Gilenya 0.5 mg dose. The following results are shown for Gilenya 0.5 mg dose vs placebo, respectively:

    • Annualized relapse rate: 0.18 vs 0.40 (P <.001)

    • Percentage of patients without relapse: 70% vs 46% (P < .001); hazard ratio of disability progression, 0.70 (95% CI, 0.52-0.96; P =.02)

    • Mean (median) number of new or newly enlarging T2 lesions over 24 months: 2.5 (0) vs 9.8 (5.0) (P <.001)

    • Mean (median) number of T1 Gd-enhancing lesions at Month 24: 0.2 (0) vs 1.1 (0) (P <.001)

    Study 2 was a 1-year randomized, double-blind, double-dummy, active-controlled study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening and at Month 12. 

    Patients were randomized to receive Gilenya 0.5 mg (N = 431), 1.25 mg (N = 426), or interferon beta-1a, 30 mcg via the intramuscular route (IM) once-weekly (N = 435) for up to 12 months. The primary endpoint was the annualized relapse rate. The key secondary endpoints were number of new and newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5-point increase for those with baseline EDSS of 5.5) sustained for 3 months.

    Results from Study 2 showed that the annualized relapse rate was significantly lower in patients treated with Gilenya 0.5 mg than in patients who received placebo. The 1.25 mg dose resulted in no additional benefit over the Gilenya 0.5 mg dose. The following results are shown for Gilenya 0.5 mg dose vs placebo, respectively:

    • Annualized relapse rate: 0.16 vs 0.33 (P <.001)

    • Percentage of patients without relapse: 83% vs 70% (P < .001); hazard ratio of disability progression, 0.71 (95% CI, 0.42-1.21; P =.21)

    • Mean (median) number of new or newly enlarging T2 lesions over 12 months: 1.6 (0) vs 2.6 (0) (P =.002)

    • Mean (median) number of T1 Gd-enhancing lesions at Month 12: 0.2 (0) vs 0.5 (0) (P <.001)

    Pooled results of Study 1 and Study 2 showed a consistent and statistically significant reduction of annualized relapse rate compared to comparator in subgroups defined by gender, age, prior MS therapy, and disease activity.

     

    Pediatric Patients (10 to less than 18 Years of Age)

    Study 4 (NCT 01892722) is a double-blind, randomized, clinical trial that compared the efficacy of once-daily oral doses of Gilenya 0.25 mg or Gilenya 0.5 mg to intramuscular interferon beta-1a in 215 pediatric patients 10 to less than 18 years of age with relapsing-remitting multiple sclerosis. The study included patients who had experienced at least 1 clinical relapse during the year prior or 2 relapses during the 2 years prior to screening, or evidence of 1 or more Gd-enhancing lesions on MRI within 6 months prior to randomization, and had an EDSS score from 0 to 5.5. 

    Neurological evaluations were scheduled at screening, every 3 months, and at the time of suspected relapses. MRI evaluations were performed at screening and every 6 months throughout the study. The primary endpoint was the annualized relapse rate.

    Results from Study 4 showed that the annualized relapse rate was significantly lower in patients treated with Gilenya than in patients who received interferon beta-1a. The following results are shown for Gilenya 0.25 mg or 0.5 mg dose vs interferon beta-1a, respectively:

    • Annualized relapse rate: 0.122 vs 0.675 (relative reduction, 81.9%; 2-sided P <.001)

    • Percentage of patients without relapse at 24 months: 86% vs 45.8% (P < .001)

    • Annualized rate of the number of new or newly enlarging T2 lesions: 4.393 vs 9.269 (relative reduction, 52.6%; 2-sided P <.001)

    • Mean number of Gd-enhancing T1 lesions per scan up to Month 24: 0.436 vs 1.282 (relative reduction, 66.0%; 2-sided P <.001)

    Gilenya Note

    Notes

    Enroll pregnant patients in the Gilenya pregnancy registry by calling (877) 598-7237.

    Gilenya Patient Counseling

    Patient Counseling

    Tell patients not to discontinue Gilenya without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidentally take more Gilenya than prescribed.

    Cardiac Effects

    • Advise patients that initiation of Gilenya treatment results in a transient decrease in heart rate.
    • Inform patients that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose, after reinitiation if treatment is interrupted or discontinued for certain periods, and after the dosage is increased.

    Risk of Infections 

    • Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking Gilenya, and that they should contact their physician if they develop symptoms of infection.
    • Advise patients that the use of some vaccines should be avoided during treatment with Gilenya and for 2 months after discontinuation.
    • Recommend to patients that they delay treatment with Gilenya until after VZV vaccination if they have not had chickenpox or a previous VZV vaccination.
    • Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

    Progressive Multifocal Leukoencephalopathy

    • Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients who received Gilenya. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months.
    • Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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.

    Macular Edema

    • Advise patients that Gilenya may cause macular edema, and that they should contact their physician if they experience any changes in their vision. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.

    Hepatic Effects

    • Inform patients that Gilenya may cause liver injury. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. 

    Posterior Reversible Encephalopathy Syndrome

    • Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae.

    Respiratory Effects

    • Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea. 

    Fetal Risk

    • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. 

    • Advise female patients of reproductive potential to use effective contraception during treatment with Gilenya and for 2 months after the final dose.

    Severe Increase in Disability After Stopping Gilenya

    • Inform patients that severe increase in disability has been reported after discontinuation of Gilenya. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of Gilenya.

    Malignancies

    • Advise patients that basal cell carcinoma and melanoma are associated with use of Gilenya. Advise patients that any suspicious skin lesions should be promptly evaluated.
    • Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor.
    • Inform patients that lymphoma has also occurred in patients receiving Gilenya.

    Persistence of Gilenya Effects After Drug Discontinuation 

    • Advise patients that Gilenya remains in the blood and continues to have effects, including decreased blood lymphocyte counts, for up to 2 months following the last dose. 

    Hypersensitivity Reactions 

    • Advise patients that Gilenya may cause hypersensitivity reactions, including rash, urticaria, and angioedema. Advise patients to contact their physician if they have any symptoms associated with hypersensitivity. 

    Pregnancy and Pregnancy Registry 

    • Instruct patients that if they are pregnant or plan to become pregnant while taking Gilenya they should inform their physician. Encourage patients to enroll in the Gilenya Pregnancy Registry if they become pregnant while taking Gilenya. 

    Cost Savings Program

    Gilenya Patient Support & Education:

    https://www.gilenya.com/ms-pill/co-pay?utm_medium=paid&utm_term=Brand_Exact%20|%20gilenya&utm_source=google&utm_campaign=Gilenya.com_Branded_Google_5.2020

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