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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-J0000-73

Original Effective Date: 03/15/08

Reviewed: 04/12/17

Revised: 05/15/17

Subject: Natalizumab (Tysabri®) IV

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:

Natalizumab (Tysabri®) is labeled for the treatment of relapsing forms of multiple sclerosis (MS) and moderately to severely active Crohn’s disease (CD). Natalizumab is a humanized monoclonal antibody that binds to alpha-4 integrin expressed on the surface of activated T-cells. Alpha-4 integrin is a selective adhesion molecule that facilitates adhesion and subsequent leukocyte migration into areas of inflammation. Pre-clinical data has demonstrated the benefits of integrin inhibition, including mucosal healing and a reduction of inflammation. Leukocyte adhesion in endothelial cells is a multistep process that involves chemokine receptors and active integrins. Ultimately, natalizumab blocks both alpha-4 subunit of alpha-4 beta-1 (vascular cellular adhesion molecule of VCAM-1) and alpha-4 beta-7 (mucosal addressin [MAD] CAM-1). The site of action is not organ specific and other sites such as the brain, bone marrow, and kidneys are affected. This has led to studies of natalizumab in diverse chronic inflammatory diseases including MS and CD.

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. An initial attack may present as a clinically isolated syndrome (CIS); individuals presenting with this syndrome are high risk for subsequent conversion to clinically definite MS (CDMS). Although a cure for MS remains elusive, several treatment options slow the progression of the disease and reduce the frequency of relapses.

In 2008, the American Academy of Neurology published an assessment of the effectiveness and safety of natalizumab in the treatment of MS. Articles reporting results from controlled clinical trials in humans were included in the analytic process for the assessment. The authors concluded that natalizumab reduces measures of disease activity including clinical relapse rate, gadolinium-enhancement, and new and enlarging T2 lesions in patients with relapsing MS. Additionally, natalizumab therapy is associated with improved measures of disease severity such as the EDSS progression rate and the T2-hyperintense and T1-ypointense lesion burden seen on MRI in patients with relapsing MS. The assessment discusses the increased risk of developing PML in natalizumab-treated patients. Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, the authors recommend that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have particularly aggressive initial disease course. Furthermore, the authors advice against combination therapy (e.g., natalizumab with interferon beta therapy), as there is no data to support combination therapy and it may increase the risk of PML.

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract and can manifest as focal or patchy inflammation confined to the bowel wall or result in complications such as fistulas or strictures. Similar to MS, a definitive cure for CD has not been established. The goals of CD therapy are to induce and maintain remission, improve quality of life and prevent complications that may occur. Treatment options are individualized and target disease location, behavior and severity. Tumor necrosis factor (TNF) alpha antagonists have been considered the mainstay in the management of CD. Natalizumab is the first non-TNF alpha antagonist approved for the treatment of CD. It represents an important option for individuals who are intolerant or have lost efficacy to all other treatments including immune modulators and TNF alpha inhibitors.

POSITION STATEMENT:

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

Initiation of natalizumab meets the definition of medical necessity when administered for the following conditions when ALL indication-specific criteria are met:

1. Multiple Sclerosis (MS)

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

b. ONE of the following:

i. The member has a highly active disease course (e.g., >2 relapses in prior year and >1 gadolinium enhancing lesion on MRI) and has never tested positive for anti-JCV antibodies

ii. The member has an inadequate response to or has a contraindication to two or more of the following:

1. Dimethyl fumarate (Tecfidera)

2. Fingolimod (Gilenya)

3. Glatiramer acetate (Copaxone, Glatopa)

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

5. Interferon beta-1b (Betaseron)

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

7. Teriflunomide (Aubagio)

c. Natalizumab will NOT be used in combination with ANY of the following:

i. Alemtuzumab (Lemtrada)

ii. Daclizumab (Zinbryta)

iii. Dimethyl fumarate (Tecfidera)

iv. Fingolimod (Gilenya)

v. Glatiramer acetate (Copaxone, Glatopa)

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

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

viii. Mitoxantrone (Novantrone)

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

x. Teriflunomide (Aubagio)

d. Natalizumab will be used as monotherapy

e. The dose does not exceed 300 mg every 28 days

2. Crohn’s Disease

a. Member’s disease is moderately to severely active

b. Member has an inadequate response to or has a contraindication to ONE or more conventional therapies (e.g., sulfasalazine, mesalamine products, aminosalicylate, corticosteroids, immunosuppressants [6-mercaptopurine], azathioprine, cyclosporine, azathioprine, cyclosporine, methotrexate)

c. Member has an inadequate response to or has a contraindication to ONE or more tumor-necrosis factor (TNF)-antagonists (e.g., adalimumab [Humira], infliximab [Remicade], certolizumab [Cimzia])

d. Natalizumab will be used as monotherapy

e. The dose does not exceed 300 mg every 28 days

Approval duration: 1 year

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

1. Member is diagnosed with EITHER of the following:

a. A relapsing form of multiple sclerosis (i.e., RRMS, SPMS, PRMS)

b. Moderately to severely active Crohn’s disease

2. Member has demonstrated a beneficial response to therapy

3. Authorization/reauthorization for natalizumab 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

4. Natalizumab will be used as monotherapy

5. The dose does not exceed 300 mg every 28 days

Approval duration: 1 year

Natalizumab IV does not meet the definition of medical necessity when administered for all other indications as there is insufficient clinical evidence to support its use, and specifically for the following:

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: Natalizumab is approved as monotherapy for the treatment of patients with relapsing forms of MS to reduce clinical exacerbation frequency and to delay physical disability accumulation. Additionally, natalizumab is approved in adult patients for the treatment of moderately to severely active CD to induce and maintain clinical response and remission in members with evidence of inflammation who have had an inadequate response to or are unable to tolerate conventional Crohn’s disease therapies and TNF-alpha inhibitors.

Recommended Dose Adjustments: At this time, dosage adjustments for renal and hepatic impairment are not indicated and it appears that no dosage adjustments are required. Natalizumab has not been adequately studied in members less than 18 years of age or over the age of 65. Natalizumab is not indicated for use in pediatric members.

Concomitant therapy: Do not use with concomitant immunosuppressants (eg, azathioprine, cyclosporine, methotrexate, 6-mercaptopurine) or concomitant inhibitors of TNF-alpha. Aminosalicylates may be continued during treatment with natalizumab.

Drug Availability: Natalizumab is available as a concentrated solution that must be diluted prior to IV infusion. The injection is supplied as a 300 mg natalizumab in 15 mL (20 mg/mL) in a sterile, single-use, preservative-free vial.

Note: Natalizumab is only available through the TOUCH® Prescribing Program, which is a restricted distribution program. Only prescribers, patients, and infusion centers enrolled in the TOUCH Prescribing Program can prescribe, receive, and infuse natalizumab. Contact the TOUCH Prescribing Program by phone (1-800-456-2255). Additional information on the TOUCH Prescribing Program is located online at www.TOUCHprogram.com

CONTRAINDICATIONS:

Natalizumab is contraindicated in members who have or have had progressive multifocal leukoencephalopathy (PML) and in members who have had a hypersensitivity reaction to natalizumab.

PRECAUTIONS/WARNINGS:

Boxed Warning

Herpes encephalitis and meningitis: Life-threatening and fatal cases have occurred. Discontinue and treat appropriately.

Hypersensitivity reactions: The use of natalizumab has been associated with serious hypersensitivity reactions (incidence <1%). Most reactions occur within two hours of the start of the infusion and symptoms often include urticarial, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Patients experiencing hypersensitivity should not be re-challenged.

Infection: Natalizumab therapy may increase the risk of infection. The most common types observed in clinical trials were pneumonia, urinary tract infection, gastroenteritis, vaginal infection, tonsillitis, and herpes infection.

Pregnancy and Nursing:

Hepatic Injury: Natalizumab has been associated with reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, which occurred as early as six days following initiation of therapy. Natalizumab should be discontinued in patients with jaundice or evidence of liver injury.

BILLING/CODING INFORMATION:

The following codes may be used to describe natalizumab therapy:

HCPCS Coding

J2323

Injection, natalizumab, 1mg

ICD-10 Diagnoses Codes That Support Medical Necessity

G35

Multiple sclerosis

K50.00 – K50.919

Crohn's disease (regional enteritis)

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:

Progressive multifocal leukoencephalopathy (PML): an opportunistic viral infection of the brain that usually leads to death or severe disability.

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

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

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

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

RELATED GUIDELINES:

Adalimumab (Humira®), 09-J0000-46
Botulinum Toxins, 09-J0000-29

Certolizumab Pegol (Cimzia®), 09-J0000-77

Dalfampridine (Ampyra™) Oral, 09-J1000-23

Fingolimod (Gilenya™), 09-J1000-30

Functional Neuromuscular Stimulation, 09-E0000-54

Immune Globulin Therapy, 09-J0000-06

Infliximab (Remicade®), 09-J0000-39

Multiple Sclerosis Self Injectable Therapy, 09-J1000-39

Small Bowel Transplant, 02-40000-18

OTHER:

None applicable.

REFERENCES:

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  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. 2017 [cited 2017-03-21]. 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 [database online]. Tampa, FL: Gold Standard, Inc.; 2017. URL: www.clinicalpharmacology-ip.com. Accessed 3/21/17.
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  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. 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=4650d12c-b9c8-4525-b07f-a2d773eca155/.
  13. Ghezzi A, Grimaldi ME, Marrosu MG, et al. Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis study group-Italian Neurological Society. 2011;32:351-58.
  14. Goodin DS, Cohen BA, O’Connor P, et al. Assessment: the use natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): Report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 2008; 71:766-73.
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COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 04/12/17.

GUIDELINE UPDATE INFORMATION:

03/15/08

New Medical Coverage Guideline.

09/15/08

Revision to guideline; consisting of revising boxed warnings regarding PML and indication under Position Statement and adding 3 new ICD-9 codes.

03/15/09

Review and revision to guideline; consisting of updating references.

02/15/10

Review and revision to guideline; consisting of revising the boxed warnings and updating references.

02/15/11

Review and revision to guideline; consisting of updating coding and references.

02/15/12

Review and revision to guideline; consisting of updating the position statement, dosage, precautions, coding, related guidelines and references.

10/15/12

Review and revision to guideline; consisting of revision of description section, position statement, and precautions/warnings section; added contraindications section, updated references.

10/15/13

Review and revision to guideline; consisting of revising position statement, updating references, program exceptions, related guidelines and definitions.

01/01/14

Revision to guideline; consisting of updating the 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 and references.

05/15/17

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

Date Printed: August 18, 2017: 08:00 PM