The FDA approved Gilenya, a Novartis Pharmaceuticals' product for relapsing multiple sclerosis. The approved labeling indicates it reduces the frequency of clinical exacerbation and delays accumulation of physical disability.
A Closer Look at New FDA Actions
Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease characterized by central nervous system (CNS) demyelination.
The FDA approved Gilenya (fingolimod), a Novartis Pharmaceuticals’ product for relapsing ms, on September 21, 2010. Its approved labeling indicates it reduces the frequency of clinical exacerbations and delays accumulation of physical disability. It joins a limited number of other agents (interferons, COPAXONE, Novantorne, Tysarbi) used to treat MS, but is the first oral treatment. Fingolimod’s mechanism of action is unknown, but probably related to its ability to block lymphocyte egress from lymph nodes once it binds to sphinosine 1-phosphate receptors. Its active metabolite fingolimod-phosphate traps T cells in lymph nodes, reduces the number of lymphocytes in peripheral blood, and prevents their subsequent migration into the CNS.1,2
Fingolimod’s half-life is approximately 14 days. It has a slow rate of absorption with Tmax of greater than 12 hours. Its volume of distribution is high and it is lipophilic. It clears slowly, and its pharmacokinetic profile is uninfluenced by age, sex, ethnicity, gender, or weight. It is not removed by dialysis or plasma exchange. Dose adjustments are unnecessary in renal or hepatic impairment.3,4
The TRANSFORMS study randomized 1292 patients with relapsing and remitting MS (RRMS) in a double-blind, parallel- group, double-dummy trial. Subjects received fingolimod 0.5 mg once daily, fingolimod 1.25 mg once daily, or interferon beta-1a (IFN b-1a) 30 mg weekly. At 1 year, researchers found no significant difference between fingolimod groups (P = 0.159); these values represent reductions in annualized relapse rate (ARR) of 52% and 38% vs IFN b-1a. Discontinuation rates were 8% to 13% for fingolimod and 11% for IFN b-1a. Further, 86% to 91% of fingolimod patients and 92% of IFN b-1a patients reported adverse events (AEs). Most common AEs were headache, nasopharyngitis, and fatigue. Serious AEs included bradycardia and atrioventricular (AV) block, usually at the first dose. Approximately half of subjects experienced infections; serious infections occurred in 0.2% to 1.7% and 1.4% of participants in the fingolimod and IFN b-1a groups, respectively.5
The FREEDOMS study randomized 1272 subjects to oral fingolimod 0.5 or 1.25 mg once daily, or placebo for 24 months. In the fingolimod 0.5 mg, fingolimod 1.25 mg and placebo groups, 7.5%, 14.2%, and 13.4%, respectively, discontinued treatment due to AEs. Lymphocyte counts decreased at 1 month by 76% for fingolimod 1.25 mg and 73% for fingolimod 0.5 mg; this depletion persisted from 1 to 12 months. Oral fingolimod 0.5 mg and 1.25 mg significantly reduced ARR by 54% and 60%, respectively, versus placebo. Both doses of fingolimod demonstrated a significant reduction in magnetic resonance imaging end points over the course of 24 months. New or enlarging T2 lesions were also reduced. The 0.5-mg dose’s safety profile appeared better than the 1.25- mg dose (similar to TRANSFORMS), and no new safety signals were reported.6
Dosing and Precautions
Before starting Gilenya, prescribers need to draw baseline complete blood count, liver transaminase, and bilirubin levels, and monitor periodically. Fingolimod may increase macular edema risk—patients should undergo ophthalmologic examination at baseline and 3 to 4 months later; if they report visual disturbance; and regularly if they have diabetes or a history of uveitis. If patients are taking antiarrhythmics, or have a history of second degree or higher AV block, sick sinus syndrome, prolonged QT interval, ischemic cardiac disease, congestive heart failure, heart rate below 55 bpm, or irregular heartbeat, an electrocardiogram is needed. Patients who have not had or been vaccinated for chicken pox should received varicella zoster virus vaccine, and wait 1 month before starting Gilenya.1
Fingolimod is dosed at 0.5 mg once daily orally; it is a hard capsule that can be taken with or without food. The first dose must be administered under supervision after pulse and blood pressure are taken. The patient must be directly observed for 6 hours for possible bradycardia. Women of childbearing potential must use contraception during and for 2 months after treatment.1
Reduction in circulating lymphocyte, which may be associated with increased risk of infection, will usually resolve within 2 months of discontinuing Gilenya, but may persist.7
Instruct patients to report symptoms of infection for up to 2 months. Gilenya’s effects on heart rate and AV conduction may recur on therapy reinitiation if the product is discontinued for 14 days or more.1
1. Gilenya [package insert]. East Hanover, NJ: Novartis; September 2010.
2. Stüve O. Knowns and unknowns in the future of multiple sclerosis treatment. J Neurol Sci.
3. Kovarik JM, Slade A, Voss B, et al. Ethnic sensitivity study of fingolimod in white and Asian subjects. Int J Clin Pharmacol Ther.
4. Mansoor M, Melendez AJ. Recent trials for FTY720 (fingolimod): a new generation of immunomodulators structurally similar to sphingosine. Rev Recent Clin Trials.
5. Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med.
6. Kappos L, Radue EW, O’Connor P, et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med.
7. Johnson TA, Shames I, Keezer M, et al. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol.
Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland.