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Date Printed: October 23, 2017: 02:06 AM

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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. 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.

09-J1000-82

Original Effective Date: 12/15/12

Reviewed: 09/13/17

Revised: 10/15/17

Subject: Teriflunomide (Aubagio®) Tablet

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS). It is characterized by triad of inflammation, demyelination, and scarring of the central nervous system and manifests as pathological (immune-mediated CNS demyelination and axonal injury) and clinical (exacerbations, disability progression) dissemination in time and space. Although the clinical course of the disease is capricious, MS has been categorized into four types: relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive-relapsing (PRMS). The most common type is RRMS, which is characterized by acute attacks followed by periods of remission.

Although a cure for MS remains elusive, several treatment options slow the progression of the disease and reduce the frequency of relapses. Currently there are nine Food and Drug Administration (FDA)-approved disease-modifying therapies (DMT) for MS. Interferon-beta (IFN-beta) (i.e., Avonex®, Rebif®, Betaseron®, Extavia®) and glatiramer acetate (Copaxone®) are commonly referred to as first-line agents. The newest DMT to gain FDA-approval is teriflunomide (Aubagio®). Teriflunomide inhibits the function of specific immune cells that have been implicated in MS and is structurally related to leflunomide (Arava®), an agent used in the treatment of rheumatoid arthritis. Although the exact mechanism by which teriflunomide exerts its therapeutic effects in MS is unknown, it is hypothesized that its presumed immunomodulatory effects are the result of reversible binding to dihydro-orotate-dehydrogenase (DHO-DH) and subsequent inhibition of pyrimidine synthesis in rapidly dividing cells such as T and B lymphocytes.

Teriflunomide was approved by the FDA in September 2012 for the treatment of individuals with relapsing forms of multiple sclerosis and is the second oral disease-modifying therapy approved. Clinical practice guidelines set forth by the American Academy of Neurology (AAN) and the Multiple Sclerosis Therapy Consensus Group (MSTCG) do not include recommendations for the use of teriflunomide, as these guidelines were updated prior to the approval of teriflunomide.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

NOTE: Aubagio, Avonex, Betaseron, Copaxone, Gilenya, Glatopa, Plegridy, Rebif and Tecfidera are preferred products for treatment of relapsing forms of multiple sclerosis.

Initiation of teriflunomide (Aubagio®) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is diagnosed with a relapsing form of multiple sclerosis (MS) (i.e., relapsing-remitting MS [RRMS], secondary-progressive MS [SPMS] with relapsing disease, progressive-relapsing MS [PRMS])

2. Teriflunomide will not be used in combination with ANY of the following:

a. Alemtuzumab (Lemtrada)

b. Daclizumab (Zinbryta)

c. Dimethyl fumarate (Tecfidera)

d. Fingolimod (Gilenya)

e. Glatiramer acetate (Copaxone, Glatopa)

f. Interferon beta-1a (Avonex, Rebif)

g. Interferon beta-1b (Betaseron, Extavia)

h. Leflunomide (Arava)

i. Mitoxantrone (Novantrone)

j. Natalizumab (Tysabri)

k. Ocrelizumab (Ocrevus)

l. Peg-interferon beta-1a (Plegridy)

3. The member does not have severe hepatic impairment (Child-Pugh Class C)

4. The dose does not exceed 14 mg daily

Approval duration: 1 year

Continuation of teriflunomide therapy meets the definition of medical necessity when ALL of the following criteria are met:

1. Member has demonstrated a beneficial response to therapy for treatment of a relapsing form of multiple sclerosis (i.e., relapsing remitting multiple sclerosis [RRMS], secondary progressive MS [SPMS], progressive-relapsing MS [PRMS])

2. Authorization/reauthorization for teriflunomide has been previously approved by Florida Blue or another health plan in the past 2 years, OR the member currently meets all indication-specific initiation criteria

3. Teriflunomide will not be used in combination with ANY of the following:

a. Alemtuzumab (Lemtrada)

b. Daclizumab (Zinbryta)

c. Dimethyl fumarate (Tecfidera)

d. Fingolimod (Gilenya)

e. Glatiramer acetate (Copaxone, Glatopa)

f. Interferon beta-1a (Avonex, Rebif)

g. Interferon beta-1b (Betaseron, Extavia)

h. Leflunomide (Arava)

i. Mitoxantrone (Novantrone)

j. Natalizumab (Tysabri)

k. Ocrelizumab (Ocrevus)

l. Peg-interferon beta-1a (Plegridy)

4. The dose does not exceed 14 mg daily.

Approval duration: 1 year

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved: Teriflunomide is approved for the treatment of members with relapsing forms of MS. The recommended dose is 7- or 14 mg orally once daily, with or without food.

Dosage Adjustments:

Monitoring (Refer to “Precautions” section for additional information)

Procedure for Accelerated Elimination: Without an accelerated elimination procedure, teriflunomide takes an average of 8 months to reach plasma concentrations less than 0.02 mg/L. Because of individual variation in drug clearance, it may take as long as 2 years. An accelerated elimination procedure can be used at any time after teriflunomide discontinuation. The following procedures are recommended in the manufacturer’s labeling.

If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.

Drug Availability: Teriflunomide is supplied as 7- and 14 mg film-coated tablets.

PRECAUTIONS:

Boxed Warnings

o Obtain transaminase and bilirubin levels within 6 months before initiation of teriflunomide and monitor transaminase levels at least monthly for 6 months.

o If drug induced liver injury is suspected, discontinue teriflunomide and perform accelerated elimination procedure.

Contraindications

PRECAUTIONS/WARNINGS

Peripheral Neuropathy: If a member develops symptoms consistent with peripheral neuropathy, evaluate member and consider discontinuing teriflunomide and using accelerated elimination procedure. Members greater than 60 years of age, with concomitant nephrotoxic medications, and diabetes may be at an increased risk of peripheral neuropathy.

Acute Renal Failure: In clinical trials, 1.2% of individuals in the teriflunomide arm had transient acute renal failure with creatinine measurement increased by 100% or more of their baseline serum creatinine, compared to 0% of individuals in the placebo arm. The increased serum creatinine occurred between 12 weeks and 2 years after the first dose. Monitor renal function in members with symptoms of renal failure.

Hyperkalemia: Monitor potassium in members with symptoms of hyperkalemia.

Hypersensitivity and Severe skin reaction: cases of anaphylaxis, angioedema, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in individuals taking leflunomide. If members administered teriflunomide develop signs and symptoms of severe allergic reaction, SJS or TEN, discontinue teriflunomide and perform an accelerated elimination procedure.

Blood pressure: teriflunomide may affect blood pressure. Blood pressure should be measured at treatment initiation and periodically during treatment. Elevated blood pressure should be appropriately managed during treatment.

Concomitant use with immunosuppressive or immunomodulating therapies: Co-administration with antineoplastic, or immunosuppressive therapies used for the treatment of MS has not been evaluated. Although safety studies in which teriflunomide was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns, the long term safety of these combinations has not been established.

Bone marrow effects: A decrease in white blood cell (WBC) count may occur in members treated with teriflunomide. In clinical trials, the decrease in WBC count occurred during the first 6 weeks and the count remained low during treatment. Although no cases of serious pancytopenia were reported in premarketing trials of teriflunomide, rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. Obtain a complete blood count (CBC) within 6 months before the initiation of teriflunomide treatment. Additional monitoring should be based on signs and symptoms suggestive of bone marrow suppression.

Risk of Infection: teriflunomide should not be initiated in members with active acute or chronic infections until the infection is resolved. If a member develops serious infection while taking teriflunomide, consider suspending treatment and using an accelerated elimination procedure.

Respiratory effects: Interstitial lung disease, including acute interstitial pneumonitis has been reported.

Tuberculosis screening: members should be screened for latent tuberculosis infection with a tuberculin skin test prior to initiating teriflunomide. The safety of teriflunomide in individuals with a positive tuberculin skin test is unknown.

Pregnancy and Lactation

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8499

Prescription drug, oral, nonchemotherapeutic, NOS

ICD-10 Diagnosis Codes That Support Medical Necessity:

G35

Multiple Sclerosis

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

Medicare Part D: Florida Blue has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

DEFINITIONS:

Relapsing-remitting multiple sclerosis (RRMS): Characterized by acute attacks followed by periods of remission; primary form of MS that occurs in approximately 85% of individuals.

Primary-progressive multiple sclerosis (PPMS): Steadily progressive course from onset with no acute attacks; occurs in 10-15% of individuals with MS.

Secondary-progressive multiple sclerosis (SPMS): An initial period of RRMS, followed by a steadily progressive course, with or without acute relapses; 75-85% of individuals diagnosed with RRMS will transition to SPMS.

Progressive-relapsing multiple sclerosis (PRMS): Steadily progressive course from onset with acute attacks, with or without recovery; occurs in less than 5% of MS individuals.

RELATED GUIDELINES:

Botulinum Toxins, 09-J0000-29
Diagnosis and Treatment of Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis, 02-35000-01

Functional Neuromuscular Stimulation, 09-E0000-54

Immune Globulin Therapy, 09-J0000-06

Multiple Sclerosis Self Injectable Therapy, 09-J1000-39

Natalizumab (Tysabri®) IV, 09-J0000-73

Ocrelizumab (Ocrevus), 09-J2000-78

OTHER:

None applicable.

REFERENCES:

  1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2016 [cited 2016-09-24].
  2. Bayer. Betaseron (interferon beta-1b) injection. 2014 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66311f74-0472-4fa3-848a-06002ca0def5/.
  3. Biogen. Avonex (interferon beta-1a) injection. 2008 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=84d42ba4-6eef-41a7-a1d1-2cc887ef118d/.
  4. Biogen. Plegridy (peginterferon beta-1a) injection. 2014 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08f0ea03-4e6d-195d-aef4-886e32befa95/.
  5. Biogen. Tecfidera (dimethyl fumarate) capsule. 2015 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=665d7e74-036c-5f68-5b67-ab84b9b49151/.
  6. Biogen. Tysabri (natalizumab) injection. 2015 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5fdde91-1989-4dd2-9129-4f3323ea2962/.
  7. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2017 [cited 2017-08-30]. Available from: http://www.clinicalpharmacology.com/.
  8. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2015-08-25]. Available from: http://clinicaltrials.gov/.
  9. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2017-08-30]. Available from: http://www.thomsonhc.com/.
  10. EMD Serono. Rebif (interferon beta-1a) injection. 2015 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fcb5d2-8fcd-44fa-a838-b84ee5f44f0f/.
  11. Freedman MS. Treatment options for patients with multiple sclerosis who have suboptimal response to interferon-β therapy. Eur J Neurol 2014;21:377-87.
  12. Genzyme. Aubagio (teriflunomide) tablet, film coated. 2017 [cited 2017-08-30]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4650d12c-b9c8-4525-b07f-a2d773eca155/.
  13. Limmroth V. Treatment of relapsing-remitting multiple sclerosis: current and future algorithms. Eur J Neurol 2014;72:35-8.
  14. Meuth SG, Gobel K, Wiendl H. Immune therapy of multiple sclerosis-future strategies. Curr Pharm Des 2012;18:4489-97.
  15. Mikol DD, Barkhof F, Chang P, et al. 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 multicenter, randomized, parallel, open-label trial. Lancet Neurol 2008;7:903-14.
  16. Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence. Available at http://www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed 09/26/2016.
  17. National Clinical Advisory Board of the National Multiple Sclerosis Society. Disease management consensus statement. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/index.aspx Accessed 08/13/2012.
  18. Novartis. Extavia (interferon beta-1b) injection. 2014 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4cfdb571-ec4c-478f-bedc-e0669eeea504/.
  19. Novartis. Gilenya (fingolimod hydrochloride) capsule. 2015 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9/.
  20. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303.
  21. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016-09-24]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  22. Perumal J, Khan O. Emerging disease-modifying therapies in multiple sclerosis. Curr Opin Neurol 2012;14(3):256-63.
  23. Sandoz. Glatopa (glatiramer acetate) injection. 2015 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5f01e40a-b6f6-40fb-b37c-3d06f1428e86/.
  24. Teva. Copaxone (glatiramer acetate) injection. 2014 [cited 2015-08-25]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa88f583-4f5f-433b-80b4-1f4c9fb28357/.
  25. Wiendl H, Toyka KV, Rieckmann R, et.al. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol 2008;255:1449-63.
  26. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014;89:225-40.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 09/13/17.

GUIDELINE UPDATE INFORMATION:

12/15/12

New Medical Coverage Guideline.

03/15/13

Revision to guideline; consisting of updating the position statement.

10/15/13

Review and revision to guideline; consisting reformatting position statement updating references.

01/01/14

Revision to guideline; consisting of updating position statement.

10/15/14

Review and revision to guideline; consisting of reformatting position statement and updating references.

01/01/15

Revision to guideline; consisting of updating position statement.

10/15/15

Review and revision to guideline; consisting of updating position statement, references.

11/01/15

Revision: ICD-9 Codes deleted.

01/01/17

Review and revision to guideline; consisting of updating position statement, precautions and references.

10/15/17

Review and revision to guideline; consisting of updating position statement and references.

Date Printed: October 23, 2017: 02:06 AM