Natalizumab (Tysabri) and natalizumab biosimilar (Tyruko) coverage
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Defines medical necessity, initial and continuation authorization, site-of-care rules, dosing references and specialty prescriber/REMS requirements for natalizumab (Tysabri) and natalizumab-sztn (Tyruko) for relapsing forms of MS and moderately to severely active Crohn's disease for Blue Cross NC members.
For CD: Added allowance for patients currently established on a biologic or systemic immunomodulator agent with demonstrated clinical benefit to qualify.
For CD: Replaced requirement of severely active disease with requirement to demonstrate moderately to severely active disease by specific symptom plus objective inflammation or other defined criteria.
Updated Site of Care medical necessity criteria to add additional bypasses for patients with history of severe adverse events or conditions increasing risk for severe adverse events.
Added natalizumab biosimilar Tyruko (natalizumab-sztn) with same FDA indications and coverage criteria as Tysabri.
Added HCPCS code Q5134 for Tyruko and removed nonspecific codes C9399/J3490/J3590.
Medical Necessity Criteria
Initial Therapy - Multiple Sclerosis
Covered when ALL of the following are met
MS disease activity or prior therapy
- Highly active disease: a. Highly active MS defined by BOTH: ≥2 relapses in the prior year; AND ONE of: ≥1 gadolinium‑enhancing lesion on MRI OR significant increase in T2 lesion load compared with prior MRI (medical record documentation required).
- Prior therapy allowances: b. ONE of: trial and inadequate response to ONE listed generic MS agent (dimethyl fumarate, fingolimod, glatiramer acetate, teriflunomide) OR intolerance/hypersensitivity to one of these OR FDA‑labeled contraindication to ALL of these OR prior treatment with ≥3 MS agents from different drug classes (medical record documentation required).
Initial Therapy - Crohn's Disease
Covered when ALL of the following are met
CD disease activity or clinical context
- Active inflammation: a. Moderately to severely active disease evidenced by symptoms consistent with active CD AND objective evidence of active inflammation on cross‑sectional imaging (MRE, CTE), intestinal ultrasound, or pelvic MRI for perianal disease; OR biomarker evidence (elevated fecal calprotectin, elevated CRP, elevated ESR, low serum albumin).
- Significant extent/upper GI involvement: b. Significant extent of disease or upper GI involvement on radiographic or endoscopic assessment (e.g., large/deep mucosal lesions, fistulas, abscess, strictures, extensive disease such as ileal involvement >40 cm or pancolitis, prior bowel resection).
- Steroid dependence or refractory: c. Corticosteroid‑dependence or refractory to oral corticosteroids.
- Established biologic benefit (policy change): d. Patient is currently established on an FDA‑approved biologic or systemic immunomodulator for CD (excluding sample use) with documented positive clinical benefit (added allowance effective 7/1/2026).
Continuation Therapy
Covered when ALL of the following are met
The FDA label and policy explicitly state that natalizumab is not for use in combination with immunosuppressants or TNF-alpha inhibitors. This limitation applies to initiation and continuation of therapy and reflects the increased risk profile (including PML) described in the prescribing information. Clinical requests that document concurrent use with these agents do not meet the FDA-labeled limitations and are excluded from coverage under this policy.
The policy prohibits concurrent use with specified combination therapies. For multiple sclerosis, patients must not receive concurrent therapy with two or more disease-modifying MS drugs (the policy lists agents such as glatiramer, interferon betas, fingolimod, teriflunomide, dimethyl/monomethyl fumarate, ofatumumab, alemtuzumab, siponimod, cladribine, ocrelizumab, ponesimod, natalizumab [Tysabri, Tyruko], diroximel fumarate, ozanimod, ublituximab, and others). For Crohn’s disease, continuation and initiation criteria require that the patient will not use the requested agent in combination with an immunomodulatory agent (examples include TNF-alpha inhibitors, JAK inhibitors, IL-4 inhibitors) or other specified immunosuppressants. Requests proposing excluded concurrent therapies are not covered.
Dosing, Units, and Billing Codes
Prior Authorization, Documentation, and Denial Triggers
Prior Authorization Required
Prior authorization is required for the requested agent. Approval will be granted when the medical necessity criteria are met and required documentation is provided.
- Prior authorization required and will be granted when ALL clinical criteria and documentation requirements are satisfied.
- Affected HCPCS/J-codes: see billing/coding section of the policy for specific codes (prior authorization applies to those codes).
Required Prior Therapy / Trials
Step therapy / prior agent requirements must be documented in the medical record. The patient must have tried and had an inadequate response, intolerance, hypersensitivity, or documented contraindication to specified prior MS agents unless they meet other high-activity or multi-agent treatment exceptions.
- The patient has tried and had an inadequate response to ONE of: dimethyl fumarate (Tecfidera generic), fingolimod (Gilenya generic), glatiramer acetate (Copaxone or Glatopa generic), or teriflunomide (Aubagio generic), with documentation; OR
- The patient has an intolerance or hypersensitivity to ONE of the above agents, with documentation; OR
- The patient has an FDA-labeled contraindication to ALL of the above agents, with documentation; OR
- The patient has been treated with at least three MS agents from different drug classes (medical record documentation required).
Required Supporting Documentation
Medical record documentation must be submitted to support the diagnosis, disease activity, prior therapy attempts or contraindications, and objective findings of disease activity.
- Diagnosis of relapsing form of MS (including clinically isolated syndrome, relapsing-remitting, or active secondary progressive) and patient age (≥18 years) must be documented.
- Functional status documentation (ability to ambulate a few steps or functional arm/hand use for ADLs).
- For highly active disease: documentation of ≥2 relapses in the prior year AND either ≥1 gadolinium-enhancing lesion on MRI or significant increase in T2 lesion load compared with prior MRI.
- Documentation of prior therapies tried, dates of treatment, clinical response, intolerances/hypersensitivity, or FDA-labeled contraindications.
- If applicable, documentation that the patient has been treated with at least three MS agents from different drug classes (include agent names and treatment dates).
- For Crohn’s disease indications (if relevant to request), documentation of symptoms consistent with active disease and objective evidence of inflammation (imaging, endoscopy, or biomarkers) as specified in policy.
Denial Triggers for Unmet Criteria
Requests will be denied if required criteria or documentation are missing, if prior therapy requirements are not met, or if disallowed combinations/age/diagnosis exclusions apply.
- Missing or insufficient medical record documentation to support diagnosis, disease activity, functional status, or objective findings (e.g., MRI reports, documentation of relapses).
- Failure to document trial and inadequate response to required prior MS agents, intolerance/hypersensitivity, or FDA contraindication as outlined in the prior therapy requirements.
- Concurrent use of two or more disease‑modifying therapies for MS (policy disallows concurrent therapy with two or more listed agents).
- Patient does not meet age requirement (e.g., under 18 for MS indication when policy requires ≥18).
- Requested agent being used in combination with excluded immunomodulatory or immunosuppressant agents contrary to policy (for CD or other indications).
- Prescriber not a specialist or lacking documented specialist consultation, or prescriber not enrolled in required REMS/TOUCH programs when applicable.
Key Definitions and Indication Details
Clinical Background
Natalizumab (Tysabri) and the natalizumab biosimilar Tyruko (natalizumab-sztn) are monoclonal antibodies indicated as monotherapy for adults with relapsing forms of multiple sclerosis (including clinically isolated syndrome, relapsing‑remitting disease, and active secondary progressive disease) and for the induction and maintenance of clinical response and remission in adults with moderately to severely active Crohn’s disease with evidence of inflammation. The drug is administered intravenously and carries a significant safety consideration for progressive multifocal leukoencephalopathy (PML)
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