Natalizumab
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Clinical coverage and utilization management criteria for natalizumab (Tysabri and biosimilar Tyruko) for Crohn's disease and relapsing forms of multiple sclerosis, including precertification and site-of-care notes, for Aetna commercial medical plans.
No material clinical or coverage changes in this revision.
Coverage Criteria for Natalizumab
FDA‑indicated and recommended use — Covered when ALL of the following are met:
Covered when ALL of the following are met:
ALL of the following
- Indication: The member has a diagnosis of moderately to severely active Crohn's disease (CD) with evidence of inflammation, OR a relapsing form of multiple sclerosis (including clinically isolated syndrome, relapsing-remitting MS, or active secondary progressive MS).
- Prior treatment failure or intolerance: For Crohn's disease, the adult member has had an inadequate response to, or is unable to tolerate, conventional CD therapies and inhibitors of tumor necrosis factor alpha (TNF-α) (e.g., infliximab, adalimumab).
- Prescriber specialty: The medication is prescribed by or in consultation with an appropriate specialist (gastroenterologist for Crohn's disease; neurologist for multiple sclerosis or clinically isolated syndrome).
- Enrollment in restricted distribution program: The member (and prescriber/infusion provider) are enrolled in and compliant with the applicable TOUCH/CD-TOUCH prescribing program and monitoring requirements as required by the FDA labeling.
- Risk assessment and testing: The member has been evaluated for risk of progressive multifocal leukoencephalopathy (PML), including baseline MRI as clinically indicated and anti‑JC virus (JCV) antibody testing performed prior to initiation and documented in the medical record.
- Concomitant medications: Natalizumab is to be used as monotherapy and not in combination with other disease‑modifying MS agents, immunosuppressants, or TNF inhibitors (concurrent use with agents such as azathioprine, 6‑mercaptopurine, methotrexate, infliximab, adalimumab is not allowed).
Per FDA labeling and product safety guidance.
- For Crohn's disease only: Documentation of clinical response or remission on therapy and plan for steroid tapering if corticosteroids are being used; if no improvement at approximately 3 months, therapy should be discontinued per CD‑TOUCH guidance.
- Safety monitoring and documentation: Provider documents monitoring plan for signs/symptoms of PML, infusion‑related adverse events, and antibody testing if a suboptimal clinical response or persistent infusion reactions occur (anti‑natalizumab antibody testing recommended when suspected).
Billing and Coding
| 86711 | Antibody; JC (John Cunningham) virus. |
| 86790 | Antibody; virus, not elsewhere specified [anti-JCV antibody testing with ELISA]. |
| 96365 | Intravenous infusion, for therapy, prophylaxis, or diagnosis; initial, up to 1 hour. |
| 96366 | Intravenous infusion; each additional hour. |
| 96367 | Intravenous infusion, concurrent infusion (if listed). |
| 96368 | Intravenous infusion, for therapy, prophylaxis, or diagnosis; therapeutic infusion requiring prolonged infusion time. |
| 96379 | Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion. |
| J2323 | Injection, natalizumab, 1 mg. |
| J0135 | Injection, adalimumab, 20 mg. |
| J0202 | Injection, alemtuzumab, 1 mg. |
| J1595 | Injection, glatiramer acetate, 20 mg. |
| J1745 | Injection, infliximab, 10 mg. |
| J1826 | Injection, interferon beta-1a, 30 mcg. |
| J1830 | Injection, interferon beta -1b, 0.25 mg. |
| J2350 | Injection, ocrelizumab, 1 mg. |
| J3245 | Injection, tildrakizumab, 1 mg. |
| J7500 | Azathioprine, oral, 50 mg. |
| J7501 | Azathioprine, parenteral, 100 mg. |
| G35 | Multiple sclerosis [relapsing, not chronic progressive]. |
| G37.8 | Other specified demyelinating diseases of central nervous system [clinically isolated syndrome]. |
| K50.00 | Crohn's disease [Adults only]. |
| K50.919 | Crohn's disease, unspecified behavior/location (range shown in policy K50.00 - K50.919). |
| C94.80 | Malignant neoplasm of lymphoid, hematopoietic and related tissue (listed among not covered). |
| G04.81 | Other encephalitis and encephalomyelitis [Rasmussen encephalitis]. |
| G36.0 | Neuromyelitis optica [Devic]. |
| G61.81 | Chronic inflammatory demyelinating polyneuritis. |
| I63.00 | Cerebral infarction [acute ischemic stroke]. |
| K51.00 | Ulcerative colitis. |
Provider Actions and Requirements
Precertification required for natalizumab and associated codes
Precertification (prior authorization) is required for natalizumab (Tysabri, Tyruko) — providers must obtain precertification before administration. Failure to obtain required precertification may result in denial or delay of coverage.
Prior authorization for indicated use
Prior authorization is required to document FDA‑indicated use and medical necessity. Prescribers must demonstrate the appropriate indication (relapsing forms of MS, clinically isolated syndrome, or moderately to severely active Crohn’s disease per policy) and that recommended prior therapies or conditions have been met.
- MS: relapsing forms (including relapsing‑remitting and active secondary progressive) or CIS
- CD: adults with moderate‑to‑severe Crohn’s disease who have had inadequate response to, or intolerance of, conventional therapies and TNF‑α inhibitors
- Codes: J2323 (natalizumab), relevant CPT/HCPCS infusion codes
Prior authorization for NTZ vs alternatives
When requesting natalizumab, providers should justify choice of natalizumab versus alternative therapies (e.g., fingolimod) using available comparative‑effectiveness evidence and individualized risk assessment; observational and indirect comparisons have limitations and may require clinical justification in the record.
- Comparative evidence: observational studies suggest NTZ may reduce relapses vs fingolimod but head‑to‑head RCTs are lacking — document rationale and prior therapy history
- Consider alternative DMTs and balance benefits vs PML risk (anti‑JCV antibody status, prior immunosuppressant/TNF exposure)
Experimental/Investigational exclusions
Use of natalizumab concurrently with other disease‑modifying MS agents, immunosuppressants, or TNF inhibitors is considered experimental and investigational and is not supported by this policy.
- Examples: concurrent use with adalimumab, infliximab, azathioprine, 6‑mercaptopurine, methotrexate
- Policy: concomitant use with other DMTs or TNF inhibitors = experimental/investigational
Required documentation, testing, and TOUCH/CD‑TOUCH enrollment
Providers must submit required clinical documentation and testing results with authorization requests, including diagnosis, prior therapies tried and responses, and anti‑JCV antibody test results when available. Failure to enroll or comply with restricted distribution/safety monitoring programs (TOUCH or CD‑TOUCH) may affect authorization.
- Documentation: diagnosis, prior biologics/immunosuppressants tried, objective response measures for CD (weight, abdominal pain, diarrhea, hematocrit) or MS disease activity
- Testing: anti‑JCV antibody testing (86790) — retest every 6 months if negative; MRI prior to initiation for MS
- Program enrollment: documentation of TOUCH (MS) or CD‑TOUCH enrollment and scheduled evaluations at 3 and 6 months, then every 6 months thereafter
EDSS documentation
EDSS scoring may be required to document disease severity and disability for MS members; ensure EDSS is completed by a neurologist and included in the medical record when relevant to the authorization.
- Include EDSS score and date of exam (scale 0–10 in 0.5 increments)
- Document clinician performing EDSS (neurologist) and how score supports medical necessity
Comparative effectiveness evidence limitations
Comparative‑effectiveness and observational evidence have limitations (no head‑to‑head RCTs versus some alternatives); reviewers may request additional clinical rationale and prior treatment history when NTZ is selected over other disease‑modifying therapies.
- Observational studies and indirect comparisons suggest potential superiority of NTZ for relapse reduction but are subject to confounding
- Operational note: provide objective prior therapy failures/intolerance and risk stratification (anti‑JCV status) to support NTZ use
Off‑label epilepsy indication unsupported
Natalizumab has been studied as adjunctive therapy for drug‑resistant epilepsy and did not meet the pre‑defined threshold for effectiveness; this off‑label indication is unsupported by current evidence and is considered experimental.
- Phase II trial (French et al, 2021) did not demonstrate significant seizure reduction versus placebo
- Policy: adjunctive therapy for drug‑resistant epilepsy = experimental/investigational
No step therapy requirements or sequencing
This policy section does not list specific step‑therapy sequencing rules; no step therapy requirements are included for natalizumab in the provided policy excerpts.
- No step therapy rules present in policy excerpts
- Site‑of‑care UM policy still applies for infusion location
Administrative notices and links
Administrative notices: policy history, review dates, links to additional resources, and disclaimers are included in the document — consult the policy history and clinical policy bulletin notes for updates.
- Effective date: 2008‑04‑11; Last review: 02/20/2024; Next review: 08/22/2024
- Links: Clinical Policy Bulletin Notes, Definitions, Review History
- Disclaimer: CPB is not a contract and may be updated
Background and Context
Natalizumab is a humanized monoclonal antibody that targets alpha‑4 integrin and is indicated as monotherapy for relapsing forms of multiple sclerosis and for induction and maintenance of response in selected adults with moderate‑to‑severe Crohn's disease. The drug carries a boxed warning for progressive multifocal leukoencephalopathy (PML); known risk factors include anti‑JCV antibody positivity, prior immunosuppressant use, and longer duration of therapy.
Definitions and Key Terms
Policy Revision History
Policy last reviewed (document status: CURRENT).
Policy became effective on this date (original effective date recorded).
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