Clinical UM Guideline

Subject:Beta Interferons or Glatiramer Acetate for Treatment of Multiple Sclerosis
Guideline #:  CG-DRUG-03Current Effective Date:  08/27/2009
Status:RevisedLast Review Date:  08/27/2009
Description

A number of drugs are available to treat various aspects of multiple sclerosis (MS). Interferon beta agents (i.e., Avonex®, Biogen Idec, Inc., Cambridge, MA; Rebif®, EMD Serono, Inc., Rockland, MA; Betaseron®, Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ; Extavia®, Novartis Pharmaceuticals Corp., East Hanover, New Jersey), and glatiramer acetate (Copaxone®, TEVA Neuroscience, Inc., Kansas, MO) are administered chronically in an effort to decrease the relapse rate and delay the progression of the disease. For the majority of patients with MS, the mainstay of treatment focuses on the use of interferon beta (IFN-B) agents or glatiramer acetate. This guideline focuses on the use of IFN beta-1a (Avonex, Rebif), IFN beta-1b (Betaseron, Extavia) and glatiramer acetate (Copaxone) for the treatment of MS.

Clinical Indications

Medically Necessary:

Treatment of MS with IFN beta-1a or IFN beta-1b is considered medically necessary for individuals with any of the following conditions:

Treatment of MS with glatiramer acetate is considered medically necessary for individuals with relapsing-remitting MS (RRMS), including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

Not Medically Necessary:

Treatment of MS with IFN-B agents or glatiramer acetate is considered not medically necessary for individuals with either of the following conditions:

Treatment of MS with glatiramer acetate is considered not medically necessary for individuals with secondary progressive MS (SPMS).

Treatment of MS with combination therapy of any IFN-B agent, glatiramer acetate, or in combination with natalizumab is considered not medically necessary for all conditions. 

Definitions

Attacks: the appearance of new symptoms or the aggravation of old ones, lasting at least twenty-four hours (synonymous with exacerbation, relapse, flare-up, or worsening); usually associated with inflammation and demyelination in the brain or spinal cord

Chronic progressive MS: describes any form of progressive MS in which there is a gradual, irreversible worsening of symptoms

Clinical lesion:  an area of inflamed or demyelinated central nervous system tissue; synonymous with plaque

Primary progressive MS (PPMS): a clinical course of MS characterized by progression of disability from onset without superimposed relapses

Progressive relapsing MS (PRMS): a primary progressive clinical course of MS characterized by clear, acute relapses, with or without full recovery from those relapses

Relapsing-remitting MS (RRMS): a clinical course of MS characterized by clearly defined, acute relapses with full or partial recovery; no disease progression or worsening of disability develops between relapses

Secondary progressive MS (SPMS): a clinical course of MS demonstrating sustained progression of physical disability occurring separately from relapses in individuals who previously had RRMS

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS 
J1595Injection, glatiramer acetate, 20 mg (Copaxone)
J1825Injection, interferon beta-1a, 33 mcg (Avonex, Rebif)
J1830Injection, interferon beta-1b, 0.25 mg (Betaseron, Extavia)
Q3025Injection, interferon beta-1a, 11 mcg for intramuscular use (Avonex, Rebif)
Q3026Injection, interferon beta-1a, 11 mcg for subcutaneous use (Avonex, Rebif)
S9559Home injectable therapy, interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment; per diem
  
ICD-9 Diagnosis 
340Multiple sclerosis
Discussion/General Information

MS is an autoimmune disease of the central nervous system (CNS). In MS, inflammation of nervous tissue causes the loss of myelin, a fatty material that acts as a protective insulation for the nerve fibers in the brain and spinal cord. This demyelination leaves multiple areas of hard scarred tissue (plaques) along the covering of the nerve cells. Another characteristic of MS is the destruction of axons, which are the long filaments that carry electric impulses away from a nerve cell. The demyelination and axon destruction disrupts the ability of the nerves to conduct electrical impulses to and from the brain, and produces the various symptoms. Common symptoms of the disease include fatigue, numbness, coordination and balance problems, bowel and bladder dysfunction, emotional and cognitive changes, spasticity, vision problems, dizziness, sexual dysfunction, and pain. Classifications of MS are relapsing remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), and secondary progressive MS (SPMS).

The treatment goal for MS is to prevent relapses and progressive worsening of the disease. To date, a cure remains elusive and current therapies fail to reverse degenerative processes and deficits. Current disease-modifying drugs are most effective for the relapsing remitting form of MS and less effective for secondary progressive decline. The American Academy of Neurology, the Multiple Sclerosis Council for Clinical Practice Guidelines and the National Multiple Sclerosis Society suggest starting disease-modifying therapy (drug treatment) in patients with relapsing remitting disease and recent relapses; however, opinions may vary widely on when to initiate treatment (American Academy of Neurology, 2002). Generally, disease-modifying therapy should be considered early in the disease course.

IFN beta-1a, IFN beta-1b and glatiramer acetate are all FDA approved disease-modifying therapies (DMTs). In 1993, the first DMT, IFN beta-1b (Betaseron) was approved for RRMS to reduce the rate and severity of relapses. This was followed by approval of IFN beta-1a (Avonex) in 1996 and glatiramer acetate (Copaxone) in 1997. Another formulation of IFN beta-1a (Rebif) was approved in 1998 in Europe and Canada and in 2002 in the United States. These drugs have been shown to delay the progression of MS, reduce the incidence of relapses and also reduce the MRI activity thought to be linked to the underlying inflammation of the disease (Freedman 2008). IFN beta-1a and IFN beta-1b are FDA approved for relapsing forms of MS and glatiramer acetate is FDA approved for RRMS. In February 2009, the U.S. FDA approved an expanded indication for glatiramer acetate to include the treatment of patients who have experienced a first clinical episode and have MRI features consistent with MS. In August 2009, the U.S. FDA approved Extavia, a new branded version of interferon beta-1b which has the same medicinal product as Betaseron.

The American Academy of Neurology (2002) recommends beta interferon (beta 1a and beta 1b) for the management of patients with RRMS, relapsing forms of secondary progressive MS, and in patients at high risk of developing clinically definite MS. They also recommend glatiramer acetate for management of patients with RRMS.

The National Clinical Advisory Board of the National Multiple Sclerosis Society Treatment Recommendations for Physicians (2008) Expert Opinion Paper states that "there are no direct comparative data to allow a fully informed choice of the best immunomodulatory drug class (interferon beta or glatiramer acetate) with which to initiate therapy in relapsing forms of MS."

Studies have demonstrated the efficacy of the beta interferon products and glatiramer acetate in the treatment of MS; however, the data is insufficient to make a recommendation regarding the use of one of the beta interferon products (Avonex, Rebif, Betaseron, and Extavia) over another. Also, the data is insufficient to make a recommendation regarding the use of the beta interferon products (Avonex, Rebif, Betaseron, and Extavia) over glatiramer acetate (Copaxone) in the treatment of RRMS.

Off Label Indications:

International Panel Criteria (also known as the McDonald Criteria) for Diagnosis of MS
Updated (Polman, 2005) 

Clinical Presentation

Additional Data Needed for MS Diagnosis

Two or more attacksa; objective clinical evidence of two or more lesions

 

Noneb

 

Two or more attacksa; objective clinical evidence of one lesion

 

Dissemination in space, demonstrated by:

  • MRIc or
  • Two or more MRI-detected lesions consistent with MS plus positive CSFd or
    • Await further clinical attacka implicating a different site

One attacka; objective clinical evidence of two or more lesions

 

Dissemination in time, demonstrated by:

  • MRIe or
  • Second clinical attacka

One attacka; objective clinical evidence of one lesion (monosymptomatic presentation; clinically

isolated syndrome)

 

Dissemination in space, demonstrated by:

  • MRIc or
  • Two or more MRI-detected lesions consistent with MS plus positive CSFd and

Dissemination in time, demonstrated by:

  • MRIe or
  • Second clinical attacka

Insidious neurological progression suggestive of MS

 

One year of disease progression (retrospectively or prospectively determined) and

Two of the following:

  1. Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP)f
  2. Positive spinal cord MRI (two focal T2 lesions)
  3. Positive CSFd

 

If criteria indicated are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is MS; if suspicious, but the criteria are not completely met, the diagnosis is "possible MS"; if another diagnosis arises during the evaluation that better explains the entire clinical presentation, then the diagnosis is "not MS".

a  An attack is defined as an episode of neurological disturbance for which causative lesions are likely to be inflammatory and demyelinating in nature. There should be a subjective report (backed up by objective findings) or objective observation that the event lasts for at least 24 hours.
b  No additional tests are required; however, if tests (MRI, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS. Alternative diagnoses must be considered. There must be no better explanation for the clinical picture and some objective evidence to support a diagnosis of MS.
c  MRI demonstration of space dissemination must fulfill the criteria (see below).
d  Positive CSF determined by oligoclonal bands detected by established methods (isoelectric focusing) different from any such bands in serum, or by an increased IgG index.
e  MRI demonstration of time dissemination must fulfill the criteria above.
f  Abnormal VEP of the type seen in MS.

 MS = multiple sclerosis; MRI = magnetic resonance imaging; CSF = cerebrospinal fluid; VEP = visual-evoked potential 

MRI Criteria for Demonstration of Space Dissemination:
Three of the following:

  1. At least one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium enhancing lesion
  2. At least one infratentorial lesion
  3. At least one juxtacortical lesion
  4. At least three periventricular lesions

Note: A spinal cord lesion can be considered equivalent to a brain infratentorial lesion; an enhancing spinal cord lesion is considered to be equivalent to an enhancing brain lesion; and, individual spinal cord lesions can contribute together with individual brain lesions to reach the required number of T2 lesions.

MRI Criteria for Demonstration of Time Dissemination:

Two methods to demonstrate dissemination in time using imaging:

  1. Detection of gadolinium enhancement at least three months after the onset of the initial clinical event, if not at the site corresponding to the initial event
  2. Detection of a new T2 lesion if it appears at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event

Diagnosis of Multiple Sclerosis in Disease with Progression from Onset:

  1. One year of disease progression (retrospectively or prospectively determined)
  2. Plus two of the following:
    1. Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP)
    2. Positive spinal cord MRI (two focal T2 lesions)
    3. Positive CSFa (isoelectric focusing evidence of oligoclonal IgG bands or increased IgG or both)

 

References

Peer Reviewed Publications:

  1. Anderson O, Elovaara I, Farkkila M, et al. Multicentre, randomized, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2004; 75:706-710.
  2. Barbero P, Verdun E, Bergui M, et al. High-dose frequently administered interferon beta therapy for relapsing-remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study. J Neurol Sci. 2004; 222(1-2):13-19.
  3. Barkhof F, Polman CH, Radue EW, et al. Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results. Arch Neurol. 2007;64(9):1292-1298.
  4. Bertolotto A, Sala A, Malucchi S, et al. Biological activity of interferon betas in patients with multiple sclerosis is affected by treatment regimen and neutralizing antibodies. J Neurol Neurosurg Psychiatry. 2004; 75(9):1294-1299.
  5. Clanet M, Kappos L, Radue EW, et al. Results of the European interferon beta-1a (Avonex) dose-comparison study. J Neurol. 2001; 248(suppl 2):II/63.
  6. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Lancet. 2001; 357(9268):1576-1582.
  7. Comi G, Filippi M, Wolinsky JS. European/Canadian Glatiramer Acetate Study Group. European/ Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging – measures disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001; 49(3):290-297.
  8. Coyle P. Results of comparative efficacy trial using two formulations of interferon beta-1a in RRMS. J Neurol Sci. 2001; 187(suppl 1):S436.
  9. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicentre study (INCOMIN). Lancet. 2002; 359(9316):1453-1460.
  10. Edgar CM, Brunet DG, Fenton P, et al. Lipoatrophy in patients with multiple sclerosis on glatiramer acetate. Can J Neurol Sci. 2004; 31(1):58-63.
  11. Freedman MS, Hughes B, Mikol DD, et al. Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison. Eur Neurol. 2008; 60(1):1-11.
  12. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized multicentre trial. Lancet. 2002; 360(9350):2018-2025.
  13. Jacobs LD, Beck RW, Simon JH, et al. CHAMPS Study Group. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. NEJM. 2000; 343(13):898-904.
  14. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for six years. Mult Scler. 2000; 6(4):255-266.
  15. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006; 67(7):1242-1249.
  16. Khan OA, Tselis AC, Kamholz JA, et al. A prospective, open-label treatment trial to compare the effect of IFN beta-1a (Avonex), IFN beta-1 (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis. Eur J Neurol. 2001; 8(2):141-148.
  17. Li DK, Zhao GJ, Paty DW, et al. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology. 2001; 56(11):1505-1513.
  18. Metz LM, Patten SB, Archibald CJ, et al. The effect of immunomodulatory treatment on multiple sclerosis fatigue. J Neurol Neurosurg Psychiatry. 2004; 75(7):1045-1047.
  19. Mikol DD, Barkhof F, Chang P, et al.; REGARD study group. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008; 7(10):903-914. Epub 2008 Sep 11.
  20. Miller A, Spada V, Beerkircher D, Kreitman RR. Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing-remitting multiple sclerosis. Mult Scler. 2008; 14(4):494-499.
  21. Pachner AR. Anti-IFNβ antibodies in INFβ-treated MS patients. Neurology. 2003; 61(Suppl 5):S1-S5.
  22. Polman C, Reingold, S, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria." Ann Neurol. 2005; 58(6):840-846.
  23. PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon beta-1a in relapsing MS. Neurology. 2001; 56(12):1628-1636.
  24. Schrempf W, Ziemssen T. Glatiramer acetate: mechanisms of action in multiple sclerosis. Autoimmun Rev. 2007; 6(7):469-475.
  25. SPECTRIMS Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology. 2001; 56(11):1496-1504.
  26. Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between three products. Neurology. 2004; 62(4):628-631.
  27. Wolinsky JS, Narayana PA, Johnson KP, et al. United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates. Multiple Sclerosis Study Group and the MRI Analysis Center. Mult Scler. 2001; 7(1):33-41.
  28. Wolinsky JS, Narayana PA, O'Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007; 61(1):14-24.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2009®. Interferon Beta and Glatiramer Acetate. Bethesda, MD: American Society of Health-System Pharmacists®, 2009.
  2. Avonex® [Product Information], Cambridge, MA. Biogen Idec, Inc.; October, 2008. Available at:  http://www.avonex.com/msavProject/avonex. portal/_baseurl/threeColLayout/SCSRepository/en_US/avonex/includes/footer/prescribe_info_med_guide.xml. Accessed on August 18, 2009.
  3. Betaseron® [Product Information], Wayne, NJ. Bayer HealthCare Pharmaceuticals Inc.; April 2008. Available at: http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf. Accessed on August 18, 2009.
  4. Copaxone® [Product Information], Kansas City, MO. TEVA Neuroscience, Inc.; February 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf. Accessed on August 18, 2009.
  5. Extavia® [Product Information], East Hanover, NJ. Novartis Pharmaceuticals Corp.; August 2009. Available at: http://www.pharma.us.novartis.com/product/pi/pdf/extavia.pdf. Accessed on August 18, 2009.
  6. Glatiramer Acetate. In: DrugPoints ® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on August 18, 2009.
  7. 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. 2002; 58(2):169-178. Available at: http://www.neurology.org/cgi/reprint/58/2/169.pdf. Accessed on August 18, 2009.
  8. Hayes, Inc. Hayes Medical Technology Directory. Interferon Beta for Multiple Sclerosis. Lansdale, PA: Hayes, Inc.; October 2004. Search updated December 2008.
  9. Interferon Beta-1a and Interferon Beta-1b. In: DrugPoints® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on August 18, 2009.
  10. National Multiple Sclerosis Society. Changing Therapy in Relapsing Multiple Sclerosis: Considerations and Recommendations of a Task Force of the National Multiple Sclerosis Society. (2008) Available at:  http://www.nationalmssociety.org/for-professionals/healthcare-professionals/publications/expert-opinion-papers/index.aspx. Accessed on August 18, 2009.
  11. Rebif® [Product Information], Rockland, MA EMD Serono, Inc.; December 2008. Available at:  http://www.mslifelines.com/_assets/pdf/Rebif_PI.pdf. Accessed on August 18, 2009.
Web Sites for Additional Information
  1. National Multiple Sclerosis Society. About MS. Available at:  http://www.nationalmssociety.org/about-multiple-sclerosis/index.aspx. Accessed on August 18, 2009.
Index

Avonex
Beta Interferons
Betaseron
Copaxone
Extavia
Glatiramer Acetate
IFN beta-1a
IFN beta-1b
Interferon Beta Agents
Rebif

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History
StatusDateAction
Revised08/27/2009Medical Policy & Technology Assessment (MPTAC) revision. Drug brand names removed from clinical indications section. Removed table of FDA approved drugs with dosing and labeling information from discussion section. Removed not medically necessary statement regarding dosages greater than approved by the U.S. Food and Drug Administration (FDA). Description, discussion, references, and index updated. Information regarding Extavia added to document contents.
Revised05/21/2009MPTAC revision. Clinical indications for glatiramer acetate updated to include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Deletion of section of not medically necessary statement for glatiramer acetate referring to those with an initial demyelinating event. Place of service section deleted. Discussion and references updated.
Reviewed02/26/2009MPTAC review. Discussion and references updated. Moved "Summary of the FDA Approved Pharmaceutical Agents for the Treatment of MS" and the "International Panel Criteria" charts to the discussion/general information section of the document. Title updated.
Reviewed08/28/2008MPTAC review. Description, discussion and references updated.
 04/01/2008References updated to reflect change from USP DI® to new DrugPoints® compendia.
Reviewed08/23/2007MPTAC review. Title revised. Clinical indications clarified. Definitions and references updated.
Revised09/14/2006MPTAC revision. Update of guideline to include concomitant usage of beta interferons and glatiramer acetate or natalizumab is considered not medically necessary.
Revised06/08/2006MPTAC revision. Update of McDonald diagnostic criteria. Coding and references updated. No change to guideline position. 
New07/14/2005MPTAC initial guideline development.