Medication Policy Manual. Topic: Gilenya, fingolimod Date of Origin: November 22, 2010

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1 Medication Policy Manual Policy No: dru229 Topic: Gilenya, fingolimod Date of Origin: November 22, 2010 Committee Approval Date: December 11, 2015 Next Review Date: December 2016 Effective Date: January 1, 2016 IMPORTANT REMINDER This Medication Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medication policy is to provide a guide to coverage. Medication Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Fingolimod (Gilenya) is an oral medication used to prevent or lessen the severity of multiple sclerosis attacks. It works by preventing certain immune cells in the body from attacking the brain and/or spinal cord. dru229.8 Page 1 of 8

2 Policy/Criteria I. Most contracts require prior authorization approval of fingolimod prior to coverage. Fingolimod may be considered medically necessary when all of the following criteria A, B, and C are met: A. A definitive diagnosis of a relapsing form of multiple sclerosis (relapsingremitting or secondary progressive multiple sclerosis) that has been established by a specialist in neurology or multiple sclerosis. AND B. Fingolimod is prescribed by, or in consultation with, a specialist in neurology or multiple sclerosis. AND C. An interferon beta product (see Appendix A) and one additional preferred disease modifying therapy [either glatiramer acetate (Copaxone) or natalizumab (Tysabri)] were documented in clinical notes to be ineffective, contraindicated, or not tolerated. Ineffectiveness is defined as meeting at least two of the following three criteria (1, 2 or 3) during treatment with one of these agents. 1. The patient continues to have clinical relapses (at least one clinical relapse within the past 12 months). 2. The patient continues to have CNS lesion progression as measured by MRI. 3. The patient continues to have worsening disability. Examples of worsening disability include, but are not limited to, decreased mobility, decreased ability to perform activities of daily living due to disease progression or an EDSS score >3.5. II. Administration, Quantity Limitations, and Authorization Period A. OmedaRx considers fingolimod to be a self-administered medication. B. When prior authorization is approved, fingolimod may be authorized in quantities of up to 30 capsules per month. C. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. III. IV. Fingolimod is considered investigational when used concomitantly with other diseasemodifying multiple sclerosis therapies (see Appendix A). Fingolimod is considered not medically necessary when used for primary progressive multiple sclerosis (PPMS). V. Fingolimod is considered investigational when used for all other conditions, including but not limited to: A. Acute ischemic stroke B. Progressive relapsing multiple sclerosis (PRMS) dru229.8 Page 2 of 8

3 Position Statement Summary - Fingolimod is used in the treatment of relapsing-remitting multiple sclerosis (RRMS). It helps decrease the frequency and severity of multiple sclerosis (MS) attacks and may delay progression of disability due to the disease. - While considered to be effective, fingolimod (Gilenya) is associated with safety concerns that are not present with other products. - Serious adverse effects, including cardiac events resulting in sudden death, have been reported with fingolimod. Careful monitoring is required. - The safety and effectiveness of fingolimod have not been studied in combination with other disease-modifying MS medications. - Fingolimod has not been studied in progressive-relapsing MS. - Safety and effectiveness of fingolimod (Gilenya) for the treatment of other conditions, including acute ischemic stroke, have not been established. - Fingolimod (Gilenya) has not been shown to be effective for the treatment of primary progressive multiple sclerosis (PPMS). - Fingolimod doses greater than 0.5 mg (one capsule) orally daily have not been shown to provide additional benefit but are associated with an increased risk of side effects. Clinical Efficacy FINGOLIMOD IN RELAPSING-REMITTING MULTIPLE SCLEROSIS - Three large, randomized controlled trials studied fingolimod in the treatment of subjects with relapsing-remitting multiple sclerosis (RRMS). * Two trials studied the risk of MS relapses and progression of disability over two years in subjects who were taking fingolimod or placebo. Approximately 60%-75% of subjects were naïve to prior disease-modifying MS therapy. [1,2] Results for reducing the risk of MS relapse were statistically significant in both study. Results for slowing the progression of disability were inconsistent. * The third study was designed to show that fingolimod is more effective than interferon beta-1a (Avonex) in preventing MS attacks and slowing the progression of disability due to MS. [3] *. * Each phase three study was two years in length, thus efficacy beyond two years is unknown. - A 2015 Cochrane network meta-analysis concluded that alemtuzumab (Lemtrada), natalizumab (Tysabri), fingolimod (Gilenya), and mitoxantrone are more effective than other drugs at preventing relapse than other agents based on moderate to high quality evidence. The authors also concluded that only natalizumab (Tysabri) shows a beneficial effect on disability progression based on moderate quality data. Alemtuzumab (Lemtrada) and mitoxantrone were also found to be more effective than other treatments at slowing disability progression but the quality of evidence was lower. dru229.8 Page 3 of 8

4 - Fingolimod has not been studied in combination with other disease-modifying MS therapies. FINGOLIMOD (GILENYA) IN OTHER FORMS OF MS - Fingolimod (Gilenya) has not been shown to be effective for PPMS. In a large, phase 3 trial in patients with PPMS, fingolimod (Gilenya) failed to reduce the risk of sustained disability progression compared to placebo. [4] - Fingolimod (Gilenya) has not been studied in PRMS Background on Multiple Sclerosis (MS) [5] - There are four clinical courses of multiple sclerosis (characterized in Table 1 below). [5] - Relapsing-remitting multiple sclerosis accounts for up to 85% of cases. Table 1: Multiple Sclerosis Forms/Clinical Course Definitions [5] Relapsing-remitting (RRMS) Secondary progressive (SPMS) Primary progressive (PPMS) Progressive relapsing (PRMS) Characterized by acute relapses that are followed by some degree of recovery; patients do not develop worsening of disability between relapses. The American Academy of Neurology (AAN) defines RRMS as the first clinical course of MS and is characterized by self-limited attacks of neurologic dysfunction. These attacks develop acutely, evolving over days to weeks. Over the next several weeks to months, most patients experience a recovery of function that is often (but not always) complete. Between attacks the patient is neurologically and symptomatically stable. Defined as sustained progression of physical disability occurring separately from relapses, in patients who previously had RRMS. The AAN defines SPMS as the second clinical course which begins as RRMS, but at some point the attack rate is reduced and the course becomes characterized by a steady deterioration in function unrelated to acute attacks. Defined as progression of disability from onset without superimposed relapses. The AAN defines PPMS as the third clinical type characterized by a steady decline in function from the beginning without acute attacks. Defined as primary progressive patients who develop acute relapses well after disease onset. The AAN defines PRMS as the fourth clinical type which also begins with a progressive course although these patients also experience occasional attacks. Safety - There is a Risk Evaluation and Mitigation Strategy (REMS) program in place for fingolimod to educate physicians and patients on some of the unique risks associated dru229.8 Page 4 of 8

5 with its use. [6] - These risks include bradyarrhythmia and atrioventricular block (slowed heart rate and delays in heart rhythm), increased risk of infections, macular edema, decrease in lung function, decreased liver function, and fetal risk. [6] - Transient asystole and unexplained death have been reported within 24 hours of the first dose of fingolimod in the post-marketing setting. - Patients must be observed for at least 6 hours after the first dose of fingolimod to monitor for signs of bradyarrhythmia and atrioventricular block. - In August 2015, the FDA released a drug safety communication stating that two cases of progressive multifocal leukoencephalopathy (PML), a rare and serious brain infection, have occurred in patients taking fingolimod (Gilenya). The prescribing information has been updated to reflect these warnings. [7,8] - Other less severe adverse effects that occur more commonly with fingolimod than placebo include headache, lower respiratory tract infections, diarrhea, back pain, hypertension, and paresthesia. [8] Guidelines The National Institute for Health and Clinical Excellence (NICE) developed guidelines to address the use of fingolimod in relapsing-remitting multiple sclerosis. [9] - Fingolimod (Gilenya) is recommended as an option for highly active relapsing-remitting multiple sclerosis (RRMS) in adult patients, or if there are ongoing severe relapses compared with the previous year despite treatment with interferon beta. - The population evaluated in this guideline is very specific and may not reflect clinical use of fingolimod (Gilenya). Additionally, the guideline was developed from the perspective of NICE, which includes cost effectiveness and manufacturer discounts into their recommendations. Other conditions - Fingolimod (Gilenya) has been studied in patients with acute ischemic stroke. Although initial results indicate some benefit, the study was very small and primarily evaluated surrogate markers. Additional larger, well-designed studies are need to confirm safety and efficacy in patients with acute ischemic stroke. [10] Dosing Considerations [8] - The FDA-approved dose of fingolimod (Gilenya) is 0.5 mg orally once per day. - Higher doses of fingolimod (Gilenya) do not provide additional benefit but are associated with a greater risk of adverse effects. - dru229.8 Page 5 of 8

6 Appendix A: Disease-Modifying Agents Used in the Treatment of Multiple Sclerosis (MS) Alemtuzumab (Lemtrada ) Fingolimod (Gilenya ) Dimethyl fumarate (Tecfidera ) Glatiramer acetate (Copaxone ) Interferon beta-1a (Avonex, Rebif ) Interferon beta-1b (Betaseron, Extavia ) Mitoxantrone (Novantrone ) Natalizumab (Tysabri ) Peginterferon beta-1a (Plegridy ) Teriflunomide (Aubagio ) Cross References Aubagio, teriflunomide, Medication Manual, Policy No. 283 Betaseron /Extavia, interferon beta-1b, Medication Manual, Policy No. 108 Lemtrada TM, alemtuzumab, Medication Manual, Policy No. 381 Plegridy TM, peginterferon beta-1a, Medication Policy Manual, policy No.376 Tecfidera, dimethyl fumarate, Medication Manual, Policy No. 299 Tysabri, natalizumab, Medication Manual, Policy No. 111 Codes Number Description HCPCS J8499 Prescription drug, oral, non-chemotherapeutic, Not Otherwise Specified HCPCS J2323 Injection, natalizumab, 1 mg HCPCS J3590 Unclassified Biologics ICD-10 G35 Multiple sclerosis dru229.8 Page 6 of 8

7 References 1. Calabresi, PA, Radue, EW, Goodin, D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Neurology Jun;13(6): PMID: Kappos, L, Radue, EW, O'Connor, P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. The New England journal of medicine Feb 4;362(5): PMID: Cohen, JA, Barkhof, F, Comi, G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. The New England journal of medicine Feb 4;362(5): PMID: Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS). [cited 11/12/2015]; Available from: 5. Goodin, DS, Frohman, EM, Garmany, GP, Jr., et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology Jan 22;58(2): PMID: Risk Evaluation and Mitigation Strategy (REMS) for Gilenya (fingolimod) 0.5 mg capsules. [cited October 25, 2010]; Available from: atientsandproviders/ucm pdf 7. FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs. [cited 11/13/2015]; Available from: 8. Gilenya [prescribing information]. East Hanover, NJ: Novartis; August National Institute for Health and Clinical Evidence (NICE). NICE technology appraisal guidance 254: Fingolimod for treatment of highly active relapsing-remitting multiple sclerosis. Issue date: April [cited 9/11/2014]; Available from: Fu, Y, Zhang, N, Ren, L, et al. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A. 2014;111: PMID: Revision Date Revision Summary 12/11/2015 Revised definition of interferon beta ineffectiveness from two clinical relapses in the past 12 months to one clinical relapse in the past 12 months. Moved PPMS from investigational to not medically necessary dru229.8 Page 7 of 8

8 Revision Date Revision Summary Added acute ischemic stroke as an investigational use dru229.8 Page 8 of 8