Multiple sclerosis:

Indications for: GILENYA

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

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)

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.

GILENYA 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 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.

GILENYA Classification:

Sphingosine 1-phosphate receptor modulator.

GILENYA 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).

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.

Note:

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

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.

Drug 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.

Generic Drug Availability:

NO

How Supplied:

Caps—30; Blister cards—7