Medication Policy Manual. Topic: Betaseron, Extavia, interferon beta-1b Date of Origin: June 18, 2004

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1 Medication Policy Manual Policy No: dru108 Topic: Betaseron, Extavia, interferon beta-1b Date of Origin: June 18, 2004 Committee Approval Date: December 12, 2014 Next Review Date: December 2015 Effective Date: January 1, 2015 IMPORTANT REMINDER This Medical 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 medical policy is to provide a guide to coverage. Medical 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 Interferon beta-1b (Betaseron and Extavia) is an immunotherapy used in the treatment of multiple sclerosis (MS). It is administered subcutaneously and helps to reduce the number of clinical exacerbations associated with this condition. dru Page 1 of 6

2 Policy/Criteria I. Most contracts require prior authorization approval of interferon beta-1b (Betaseron, Extavia) prior to coverage. Interferon beta-1b (Betaseron, Extavia) may be considered medically necessary in patients with relapsing-remitting or secondary-progressing multiple sclerosis when treatment with one of the following is ineffective or not tolerated: A. Avonex (interferon beta-1a). OR B. Rebif (interferon beta-1a). II. III. Administration, Quantity Limitations and Authorization Period A. OmedaRx considers interferon beta-1b (Betaseron, Extavia) to be a selfadministered medication. B. When prior authorization is approved, interferon beta-1b (Betaseron, Extavia) may be authorized in quantities of 15 vials (one 0.3 mg vial injected subcutaneously every other day) 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. Interferon beta-1b is considered investigational when used for all other conditions, including but not limited to clinically isolated syndrome. Position Statement Summary - All interferon beta formulations (interferon beta-1a and interferon beta-1b) and glatiramer acetate decrease the number of attacks in patients with relapsing remitting multiple sclerosis. [2, 7-8] - There is no reliable evidence of increased efficacy or safety of one interferon beta product over another in reducing the signs and symptoms of multiple sclerosis or slowing the progression of disease. [1, 9-11] - Betaseron and Extavia both contain the same formulation of interferon beta-1b. The only difference between the products is their packaging. - Interferon beta-1b (Betaseron, Extavia) is approved at the titrated dose of 0.25 mg (one 0.3 mg vial) injected subcutaneously every other day. Clinical efficacy - There are several randomized, controlled trials comparing the efficacy of the different interferon beta products in the treatment of relapsing-remitting multiple sclerosis. The studies contain sufficient flaws (e.g., open-label design, large proportion of patients not dru Page 2 of 6

3 included in the efficacy analysis) rendering conclusions regarding the comparative efficacy unreliable. [9-11, 14] - Extavia and Betaseron are identical formulations of interferon beta-1b. In fact, the FDA approved Extavia based on clinical studies that were conducted with Betaseron. - Evidence for interferon beta-1b in clinically isolated syndrome is limited to one small randomized trial. Long-term data from large randomized, controlled trials are needed to adequately assess efficacy and safety of interferon beta-1b in this population. [15] Background on Multiple Sclerosis (MS) [2] - There are four clinical courses of multiple sclerosis (characterized in Table 1 below). - Relapsing-remitting forms of multiple sclerosis account for up to 85% of cases. Table 1: Multiple Sclerosis Forms/Clinical Course Definitions [2] 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. dru Page 3 of 6

4 Guidelines and Dosing Considerations - The American Academy of Neurology Clinical Practice Guidelines on the treatment of Multiple Sclerosis and a Cochrane analysis do not clearly indicate that one interferon beta product is superior to another on the basis of clinical trial evidence. [2, 7] - The relationship between neutralizing antibody (NAb) formation and subsequent effects on clinical efficacy and safety of the interferon products is not entirely understood and remains controversial. However, studies suggest that the presence of NAbs against interferon beta reduce the clinical efficacy of the drug and should therefore play a role in treatment decisions. [3] - According to FDA approved package labeling of the three commercially available interferon beta products, the immunogenicity of each product (formation of NAbs) in controlled clinical trials are as follows: * Interferon beta-1b (Betaseron, Extavia ): 45% [4] * Interferon beta-1a (Rebif ): 24% [5] * Interferon beta-1a (Avonex ): 5% [6] - There is no reliable evidence to support superior clinical outcomes when interferon beta- 1b is given in dosages greater than what is recommended in the prescribing information (package insert) and approved by the Food and Drug Administration (FDA). [14] The recommended dosage is 0.25 mg injected subcutaneously every other day. [4] 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 ) dru Page 4 of 6

5 Cross References Self-Administered Injectables, Medication Manual, Policy No. 110 Aubagio, teriflunomide, Medication Manual, Policy No. 283 Tecfidera, dimethyl fumarate, Medication Manual, Policy No. 299 Gilenya, fingolimod, Medication Manual, Policy No. 229 Lemtrada, alemtuzumab, Medication Manual, Policy No. 381 Plegridy, peginterferon beta-1a, Medication Policy Manual, Policy No.376 Tysabri, natalizumab, Medication Manual, Policy No. 111 Codes Number Description HCPCS J1830 Injection, Interferon beta 1b, 0.25mg HCPCS J2323 Injection, natalizumab, 1 mg HCPCS J3590 Unclassified Biologics References 1. Vartanian T. "An examination of the results of the EVIDENCE, INCOMIN and phase III studies of interferon beta products in the treatment of multiple sclerosis." Clin Ther 2003;25 (1): Goodin DS, Frohman EM, Garmany GP, 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 2002;58: Sorensen PS, Ross C, Clemmesen KM, et al. "Clinical importance of neutralizing antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis." Lancet 2003;362: Betaseron (interferon beta-1b) Prescribing Information. Berlex Laboratories; Montville, NJ, September Rebif (interferon beta-1a) Prescribing Information. Serono, Inc.; Rockland, MA, February Avonex (interferon beta-1a) Prescribing Information. Biogen IDEC, Inc.; Cambridge, MA, March Rice G PA, Incorvaia B, Munari L, Ebers G, Polman C, D Amico R, Filippini G. Interferon in relapsing-remitting multiple sclerosis. The Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD DOI: / CD Munari L, Lovati R, Boiko A. Therapy with glatiramer acetate for multiple sclerosis. The Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD DOI: / CD Durelli L, Verdun E, Barbero P, Bergui M, Versino E, et al.; Independent Comparison of Interferon (INCOMIN) Trial Study Group. Every-other-day interferon beta-1b versus onceweekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicentre study (INCOMIN). Lancet. 2002;359(9316): dru Page 5 of 6

6 10. Koch-Henriksen N, Sørensen PS, Christensen T, Frederiksen J, Ravnborg M, et al.; Danish Multiple Sclerosis Group. A randomized study of two interferon-beta treatments in relapsing-remitting multiple sclerosis. Neurology. 2006;66(7): Epub 2006 Mar Etemadifar M, Janghorbani M, Shaygannejad V. Comparison of Betaferon, Avonex, and Rebif in treatment of relapsing-remitting multiple sclerosis. Acta Neurol Scand. 2006;113(5): Copaxone (glatiramer acetate) Prescribing Information. TEVA Neuroscience, Inc., Kansas City, MO. August Extavia (interferon beta-1b) Prescribing Information. Novartis Pharmaceuticals Corp.: East Hanover, NJ; March O'Connor P, Filippi M, Arnason B, Comi G, Cook S, et al.; BEYOND Study Group. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsingremitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol Oct;8(10): Erratum in: Lancet Neurol Nov;8(11): Nagtegaal, G. J., C. Pohl, et al. (2014). "Interferon beta-1b reduces black holes in a randomised trial of clinically isolated syndrome." Mult Scler 20(2): dru Page 6 of 6