Medical Drug Criteria

Policy Num:     P1.002.008
Policy Name:   Tysabri (natalizumab)
Policy ID:          [P1.002.008]  [Ac / FB / M+ / P+]  [0.00.00]

Last Review:     December 19, 2025
Next Review:     December 20, 2026
 

Related Policies:

Tysabri (natalizumab)

Summary

Natalizumab (Tysabri) 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.

Policy Statements

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

A. Multiple Sclerosis (MS)
1. Member is diagnosed with ONE of the following
a. Relapsing-remitting MS [RRMS]
b. Active secondary-progressive MS [SPMS]
c. First clinical episode and member has MRI features consistent with MS

2. Natalizumab will NOT be used in combination with ANY of the following:
a. Alemtuzumab (Lemtrada)
b. Cladribine (Mavenclad)
c. Dimethyl fumarate (Tecfidera)
d. Diroximel fumarate (Vumerity)
e. Fingolimod (Gilenya, Tascenso ODT)
f. Glatiramer acetate (Copaxone, Glatopa)
g. Interferon beta-1a (Avonex, Rebif)
h. Interferon beta-1b (Betaseron, Extavia)
i. Mitoxantrone (Novantrone)
j. Monomethyl fumarate (Bafiertam)
k. Ocrelizumab (Ocrevus)
l. Ofatumumab (Kesimpta)
m. Ozanimod (Zeposia)
n. Peg-interferon beta-1a (Plegridy)
o. Ponesimod (Ponvory)
p. Rituximab (Rituxan or biosimilars)
q. Siponimod (Mayzent)
r. Teriflunomide (Aubagio)
s. Ublituximab (Briumvi)

3. Natalizumab will be used as monotherapy

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

B. Crohn’s Disease
1. Member’s disease is moderately to severely active
2. Member has tested negative for anti-JCV antibodies in the past 6 months
3. 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, methotrexate)
4. Member has an inadequate response to or has a contraindication to ONE or more tumornecrosis factor (TNF)-antagonists (e.g., adalimumab [Humira], infliximab [Remicade],certolizumab [Cimzia])
5. Natalizumab will be used as monotherapy
6. The dose does not exceed 300 mg every 28 days

Approval duration: 1 year

Policy Guidelines

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. RRMS, active SPMS or clinically isolated syndrome
b. Moderately to severely active Crohn’s disease

2. Member has demonstrated a beneficial response to therapy
3. Member has been tested for anti-JCV antibodies in the past 6 months
4. Authorization/reauthorization for natalizumab has been previously approved by Florida Blue or another health plan in the past 2 years, OR the member previously met all indication-specific initiation criteria
5. Natalizumab will be used as monotherapy
6. 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:

Natalizumab for chronic progressive multiple sclerosis.

Dosage/Administration

FDA-Approved: Natalizumab is approved as monotherapy for the treatment of patients with relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. Physicians should consider whether the expected benefit is sufficient to offset the risk of developing progressive multifocal leukoencephalopathy (PML).

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. Natalizumab should not be used in combination with immunosuppressants or TNF-alpha inhibitors.

Natalizumab should be administered as a 300 mg intravenous (IV) infusion given over 1 hour every 4 weeks. It should not be administered as an IV bolus or IV push.

Natalizumab should be administered within 8 hours of preparation.

Members should be observed during the infusion and post-infusion for the first 12 infusions for one hour after the infusion is complete. For patients without evidence of hypersensitivity reaction, observe post-infusion according to clinical judgement for the 13th and subsequent infusions. Note: In CD, discontinue natalizumab therapy in members that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in members that cannot discontinue chronic concomitant steroids within six months of starting therapy.

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.

1. Quantity Limit (max daily dose) [NDC Unit]:  

·         Tysabri 300 mg/15 mL vial for injection: 1 vial per 28 days

2. Max Units (per dose and over time) [HCPCS Unit]:

·         300 billable units every 28 days

required medical information

• Physician has assessed baseline disease severity utilizing an objective measure/tool;

exclusion criteria

N/A

other criteria

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA): N/A

Population Reference No. 1

References

1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2017[cited 2017-03-21].
2. Biogen. Tysabri (natalizumab) injection. 2025 [cited 2025-05-24]. 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/.
3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2025. URL:www.clinicalpharmacology-ip.com. Accessed 05/24/25.
4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2015-08-25]. Available from: http://clinicaltrials.gov/.
5. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically[cited 2025-05-24].
6. Freedman MS. Treatment options for patients with multiple sclerosis who have suboptimal response to interferon-β therapy. Eur J Neurol 2014;21:377-87.
7. 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.
8. 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 andtechnology assessment subcommittee of the American Academy of Neurology. Neurology 2008;71:766-73.
9. Hayes, Inc. Hayes Alert. MS Drug Available Again with New Restrictions, June 5, 2006. Lansdale, PA:Hayes, Inc. 2006.

10. Hayes, Inc. Hayes New-Government. FDA Approves Tysabri for the Treatment of Moderate to Severe Crohn’s Disease. January 17, 2008. Lansdale, PA: Hayes, Inc. 2008.
11. Kappos L, Bates D, Edan G, et al. Natalizumab treatment for multiple sclerosis: updatedrecommendations for patient selection and monitoring. Lancet Neurol 2011;10:745-58.
12. Limmroth V. Treatment of relapsing-remitting multiple sclerosis: current and future algorithms. Eur J Neurol 2014;72:35-8.
13. Lublin FD, Reingold, SC, Cohen JA et al. Defining the clinical course of multiple sclerosis. Neurology.2014; 83: 278-286.
14. MacDonald JK, McDonald JWD. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2006, Issue 3.
15. Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence. Available at http://www.nationalmssociety.org/getmedia/5ca284d3-fc7c4ba5-b005 ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed 09/26/2016.
16. National Clinical Advisory Board of the National Multiple Sclerosis Society. Disease management consensus statement. Available at http://www.nationalmssociety.org/about-multiplesclerosis/what-we-know-about-ms/treatments/index.aspx Accessed 08/13/2012.
17. National Multiple Sclerosis Society. Available at http://www.nationalmssociety.org Accessed 10/02/19.
18. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2025 [cited 2025-04-24]. Available from:http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
19. Pucci E, Guiliani G, Solari A, et al. Natalizumab for relapsing-remitting multiple sclerosis (review).Cochrane Database of Systematic Reviews 2011, Issue 10.
20. Rae-Grant A, Day GS, Marrie RA et al. Practice guideline: Disease-modifying therapies for adults with multiple sclerosis: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. April 2018. Available at:https://www.aan.com/Guidelines/home/GuidelineDetail/898.
21. 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.
22. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014;89:225-40.

Codes

Policy History