Health Net zanubrutinib coverage update

Coverage Criteria for Zanubrutinib (Brukinsa)

Initial approval general criteria

Covered when ALL of the following are met for the specified diagnosis

General requirements: Prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; provider submits documentation supporting that member meets the diagnosis and any indication‑specific requirements; for brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced; prescribed regimen must be FDA‑approved or recommended by NCCN or supported by peer‑reviewed literature for off‑label uses.

Documentation of indication, prior therapies, and mutation/progression status should be provided when required.

Dose rules: Dose does not exceed 320 mg (4 capsules or 2 tablets) per day; if co‑administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone), dose may be up to 640 mg (8 capsules or 4 tablets) per day; doses for off‑label uses must be supported by practice guidelines or peer‑reviewed literature.320 mg standard; 640 mg with moderate CYP3A4 inducer

Mantle cell lymphoma (MCL)

Mantle Cell Lymphoma (MCL) specific criteria — must meet ALL

MCL specific: Diagnosis of mantle cell lymphoma (MCL); prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; prescribed as one of the following: a) single‑agent zanubrutinib after at least one prior therapy (see Appendix B for therapeutic alternatives), b) in combination with rituximab, c) in combination with obinutuzumab (Gazyva) and venetoclax (Venclexta), or d) as a component of the TRIANGLE regimen; for members with disease positive for BTK C481S mutation, there must be no prior disease progression on ibrutinib (Imbruvica); brand‑to‑generic requirement and dose limits apply.

Prior therapy requirement for single‑agent use; combination options and TRIANGLE regimen added per policy updates.

Waldenström's macroglobulinemia / LPL

Waldenström's macroglobulinemia (WM) / LPL — must meet ALL

WM/LPL specific: Diagnosis of Waldenström's macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL); prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; prescribed as single‑agent zanubrutinib or in combination with rituximab; zanubrutinib must not be prescribed concurrently with ibrutinib (Imbruvica) or acalabrutinib (Calquence) where specified by indication rules; brand‑to‑generic requirement and dose limits apply.

LPL is listed as an off‑label indication per NCCN compendium guidance; prescriber must submit supporting evidence for off‑label uses.

CLL / SLL

Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) — must meet ALL

CLL/SLL specific: Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; may be prescribed as single‑agent zanubrutinib or, for histologic Richter transformation to diffuse large B‑cell lymphoma, in combination with Tevimbra as specified; for disease positive for BTK C481S mutation there must be no prior disease progression on ibrutinib (Imbruvica); brand‑to‑generic requirement and dose limits apply.

C481S/mutation and prior Imbruvica progression rules added per 1Q2023 updates.

Follicular lymphoma (FL)

Follicular Lymphoma (FL) — must meet ALL

FL specific: Diagnosis of follicular lymphoma (FL); prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; disease is relapsed, refractory, or progressive; prescribed in combination with obinutuzumab (Gazyva) after two or more prior lines of systemic therapy; brand‑to‑generic requirement and dose limits apply.

FL indication added as an FDA‑approved indication (accelerated approval); prescriber must document prior lines of therapy.

Hairy cell leukemia (off-label)

Hairy Cell Leukemia (off‑label) — must meet ALL

Hairy cell leukemia specific: Diagnosis of hairy cell leukemia; prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; disease is relapsed or refractory; prescribed as single‑agent zanubrutinib; prescribed regimen must be FDA‑approved or recommended by NCCN or supported by peer‑reviewed literature for off‑label use; dose must be within FDA maximums or supported by guidelines.

Off‑label indication; approval criteria updated per NCCN guidance.

Indication-specific coverage criteria (summary)

Coverage is provided when criteria specific to the FDA/NCCN‑approved indication are met, including prior therapy requirements, mutation status, and combination/monotherapy rules per indication.

Indication alignment: Requested use must match an FDA‑approved or NCCN‑supported indication for zanubrutinib; prescriber must document diagnosis and prior therapies; mutation (e.g., BTK C481S) or progression status must be documented when required.

Policy history documents additions and alignment with NCCN/FDA across 2021–2025.

Permitted dosing options: Typical dosing regimens include 160 mg PO twice daily or 320 mg PO once daily; maximum dosing adjustments permitted when co‑administered with a moderate CYP3A4 inducer (up to 640 mg/day).

See dosing/quantity limits.

Mutation/prior BTKi rules: For MCL and CLL/SLL when BTK C481S mutation is present, there must be no prior disease progression on ibrutinib (Imbruvica); documentation of prior BTKi therapy and progression status is required.

Added per 1Q2023 update.

Non‑FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider supplies sufficient documentation of efficacy and safety consistent with off‑label use policies. Submit supporting evidence such as peer‑reviewed literature, practice guideline recommendations (for example, NCCN), and relevant clinical data per the applicable off‑label use policies (CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace, or CP.PMN.53 for Medicaid).

Policy history documents prior restrictions on concurrent prescribing of zanubrutinib (Brukinsa) with other BTK inhibitors and subsequent revisions. Earlier updates added language preventing co‑prescription with other BTK inhibitors for certain indications; later annual reviews and RT4 updates removed or modified those restrictions depending on indication and monotherapy rules. The 1Q2022–1Q2023 reviews specifically aligned monotherapy requirements and removed blanket contraindications to concurrent BTK inhibitor use for select indications while adding mutation‑ and prior‑BTKi progression–related requirements for MCL and CLL/SLL.

Requests that do not meet the indication‑specific criteria in this policy may be considered not medically necessary and denied. Examples include missing required prior therapies, lack of documentation of required mutation or progression status (for example BTK C481S and prior progression on ibrutinib where applicable), or use that does not match the FDA‑approved or NCCN‑supported regimen/combination for the diagnosis. Providers should supply chart notes, prior therapy history, and mutation/progression evidence to support approvals.

Initial Therapy Requirements by Diagnosis

Initial therapy

Initial authorization requirements by diagnosis

Initial therapy general: Diagnosis meets the listed indication‑specific criteria; prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; dose limits as specified; brand‑to‑generic requirement applies for brand requests unless contraindicated; prescribed regimen must be FDA‑approved or NCCN‑recommended or supported by peer‑reviewed literature for off‑label use.

See individual diagnosis nodes for specifics.

Initial dosing: Typical initial dosing regimens include 160 mg orally twice daily (160 mg PO BID) or 320 mg orally once daily (320 mg PO QD).

Maximum daily dose 320 mg; up to 640 mg with moderate CYP3A4 inducer.

Initial therapy/dosing

Initial therapy/dosing — rules vary by indication and may require prior therapies or specific mutation status

Continued Therapy and Approval Duration

Continued therapy

Criteria for continued therapy

Continued therapy: Member is currently receiving zanubrutinib via the plan benefit or documentation shows member has received zanubrutinib for a covered indication for at least 30 days; member is responding positively to therapy per prescriber assessment; brand‑to‑generic requirement applies; new or continued dose does not exceed 320 mg/day (or 640 mg/day with a moderate CYP3A4 inducer) unless supported by guidelines or peer‑reviewed literature.

Prescriber must submit documentation of ongoing benefit and response.

Continuation therapy/approval duration

Continuation approvals and durations have been revised over time; approval durations vary by line of business.

Duration rules: Commercial: approval duration standardized to 12 months or the duration of the request, whichever is less; Medicaid/HIM: typically 6 months for initial approvals and 12 months for continuation in some references—follow benefit‑specific rules documented in the policy.

Policy history documents revisions to approval durations (1Q2022–1Q2025).

Dosing Limits and Coding Notes

inv-11: Maximum daily dose — 320 mg/day (standard); 640 mg/day if co-administered with a moderate CYP3A4 inducer

Maximum daily dose (standard)320 mg/day (does not exceed 320 mg; 4 capsules or 2 tablets per day)

Maximum daily dose (with moderate CYP3A4 inducer)640 mg/day when co-administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone)

Common dosing regimens160 mg PO twice daily or 320 mg PO once daily (per dosing section)

inv-12: Maximum daily dose note duplicate — 320 mg/day (or 640 mg/day when co-administered with a moderate CYP3A4 inducer)

Stated dose limit320 mg/day (or 640 mg/day when co-administered with a moderate CYP3A4 inducer)

Tablet/capsule equivalence320 mg = 4 capsules or 2 tablets; 640 mg = 8 capsules or 4 tablets

Prior Authorization, Documentation, and Step Requirements

Prior Authorization

Prior Authorization Required

Prior authorization may be required. Requests for zanubrutinib (Brukinsa/brand or generic) must include documentation that the member meets the applicable clinical criteria in this policy and any applicable LOB-specific prior authorization rules.

Prior authorization is required for commercial and Medicaid/HIM lines of business per plan rules.
Prescribed regimen must be FDA‑approved or recommended by NCCN; off‑label uses require supporting evidence (peer‑reviewed literature or guidelines).

Documentation Required

Provider must submit supporting clinical documentation with the prior authorization request. Lack of adequate documentation may result in denial.

Acceptable documentation includes office chart notes, treatment history, pathology reports, laboratory results, mutation testing (e.g., BTK C481S), and rationale for off‑label use.

Step Therapy and Substitution Rules

Requirement	Details
Brand-to-generic substitution	For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced.
Coverage status	Requirement applies to approvals and continuations across indications unless prescriber documents a contraindication or intolerance to the generic product.

Requirement	Documentation needed
Prior therapies	Provider must document prior systemic therapies relevant to the requested indication (for example prior anti‑CD20 therapy for MZL; prior lines of systemic therapy for FL).
Progression / BTK mutation status	When required by indication (e.g., MCL and CLL/SLL), document progression status on prior BTK inhibitor therapy and BTK C481S mutation status; for C481S positive disease, documentation that member has not had previous disease progression on ibrutinib (Imbruvica) is required.
Supporting records	Submit office chart notes, laboratory results, and other clinical information to verify prior treatments, progression, and mutation testing as applicable to support authorization decisions.

Quantity Limits and Dosing

inv-34: zanubrutinib standard quantity limit — 320 mg/day

Quantity limit (standard)320 mg/day

Typical daily regimens160 mg PO BID or 320 mg PO QD (per dosing guidance)

Formulation equivalence320 mg corresponds to 4 capsules or 2 tablets

inv-35: zanubrutinib with moderate CYP3A4 inducer — 640 mg/day

Quantity limit with CYP3A4 inducer640 mg/day when co-administered with a moderate CYP3A4 inducer (policy lists bosentan, efavirenz, phenobarbital, primidone)

Tablet/capsule equivalence at this dose640 mg = 8 capsules or 4 tablets

Use condition

Background on Zanubrutinib

Zanubrutinib (Brukinsa) is a Bruton tyrosine kinase (BTK) inhibitor indicated for several B‑cell malignancies including mantle cell lymphoma, Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma in specified combinations. Typical oral dosing regimens include 160 mg PO BID or 320 mg PO QD, with a standard maximum of 320 mg/day and an allowance up to 640 mg/day when co‑administered with a moderate CYP3A4 inducer. Policy updates over multiple annual reviews have added indications, aligned criteria with NCCN/FDA guidance, and clarified monotherapy, prior‑therapy, and mutation‑related requirements.

Definitions and Acronyms

inv-22: BTK definition

TermBTK

DefinitionBruton tyrosine kinase

ContextClass of kinases targeted by zanubrutinib (BTK inhibitor)

inv-23: MCL definition

TermMCL

DefinitionMantle cell lymphoma (B-cell lymphoma subtype)

Policy-specific notesMay be prescribed as single agent after ≥1 prior therapy, in combination with rituximab/Gazyva+Venclexta, or as component of TRIANGLE regimen; BTK C481S mutation rules apply

Site of Care and Administration

Note

Oral outpatient (home) administration — follow plan site‑of‑care rules

Zanubrutinib is an oral agent intended for outpatient/home administration; providers must follow plan‑specific site‑of‑care policies and benefits when prescribing for home use.

Oral outpatient administration is standard; verify member benefits and site‑of‑care rules.

OpenPayer

Zanubrutinib (Brukinsa) coverage