CurrentmhnPolicy CP.PHAR.467

Clinical Policy: Zanubrutinib (Brukinsa)

Medical necessity and prior authorization criteria for zanubrutinib (Brukinsa) for adults with specified B‑cell malignancies and certain off‑label lymphoma indications; applies to Centene‑affiliated health plans across listed lines of business.

Policy Summary

Payermhn

PolicyClinical Policy: Zanubrutinib (Brukinsa)

Policy CodePolicy CP.PHAR.467

Change TypeNo material changes

Effective Date03.01.20

Next Review Date

Key ActionProvider must submit clinical documentation (office notes, labs, other information) showing the member meets all approval criteria and obtain prior authorization.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Commercial, HIM, Medicaidapplicable lines of business

320 mg/daystandard max daily dose

640 mg/daymax with CYP3A4 inducer

12 monthstypical approval duration

Coverage Criteria for Zanubrutinib (Brukinsa)

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

MCL Initial Therapy Criteria: 1. Diagnosis of mantle cell lymphoma (MCL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed in one of the following ways: a) as a single‑agent therapy and member has received ≥ 1 prior therapy; b) in combination with rituximab; c) in combination with Gazyva (obinutuzumab) and Venclexta (venetoclax); d) as a component of the TRIANGLE regimen. 5. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 6. If disease is positive for BTK C481S mutation, member has not had previous disease progression on Imbruvica. 7. Request does not exceed health plan‑approved quantity limit, if applicable. 8. Request meets one of the following dosing criteria: a) dose does not exceed 320 mg per day; b) if co‑administered with a moderate CYP3A4 inducer, dose does not exceed 640 mg per day; c) dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 9. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial: Waldenström's Macroglobulinemia / LPL

Covered when ALL of the following are met:

WM/LPL Initial Therapy Criteria: 1. Diagnosis of Waldenström's macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed in one of the following ways: a) as a single‑agent; b) in combination with rituximab. 5. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 6. Brukinsa is not prescribed concurrently with Imbruvica or Calquence. 7. Request does not exceed health plan‑approved quantity limit, if applicable. 8. Request meets one of the following dosing criteria: a) dose does not exceed 320 mg per day; b) if co‑administered with a moderate CYP3A4 inducer, dose does not exceed 640 mg per day; c) dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 9. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial: Marginal Zone Lymphoma

Covered when ALL of the following are met:

MZL Initial Therapy Criteria: 1. Diagnosis of one of the following marginal zone lymphoma (MZL) subtypes: a) gastric MALT lymphoma; b) nongastric MALT lymphoma (noncutaneous); c) nodal MZL; d) splenic MZL. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed as single‑agent therapy. 5. Disease is relapsed, refractory, or progressive. 6. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 7. Member has received ≥ 1 line of systemic therapy including an anti‑CD20 agent (e.g., rituximab). 8. Request does not exceed health plan‑approved quantity limit, if applicable. 9. Request meets one of the following dosing criteria: a) dose does not exceed 320 mg per day; b) if co‑administered with a moderate CYP3A4 inducer, dose does not exceed 640 mg per day; c) dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 10. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial: Chronic Lymphocytic Leukemia / SLL

Covered when ALL of the following are met:

CLL/SLL Initial Therapy Criteria: 1. Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed in one of the following ways: a) as a single‑agent therapy; b) in combination with Tevimbra for histologic (Richter) transformation to diffuse large B‑cell lymphoma; c) in combination with Venclexta (venetoclax). 5. If disease is positive for BTK C481S mutation, member has not had previous disease progression on Imbruvica. 6. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 7. Request does not exceed health plan‑approved quantity limit, if applicable. 8. Request meets one of the following dosing criteria: a) dose does not exceed 320 mg per day; b) if co‑administered with a moderate CYP3A4 inducer, dose does not exceed 640 mg per day; c) dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 9. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial: Follicular Lymphoma (with obinutuzumab)

Covered when ALL of the following are met:

FL Initial Therapy Criteria: 1. Diagnosis of follicular lymphoma (FL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed in combination with Gazyva (obinutuzumab). 5. Disease is relapsed, refractory, or progressive. 6. Member has received ≥ 2 prior lines of systemic therapy. 7. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 8. Request does not exceed health plan‑approved quantity limit, if applicable. 9. Request meets one of the following dosing criteria: a) dose does not exceed 320 mg per day; b) if co‑administered with a moderate CYP3A4 inducer, dose does not exceed 640 mg per day; c) dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 10. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial: Hairy Cell Leukemia (Off‑Label)

Covered when ALL of the following are met:

Hairy Cell Leukemia Off‑Label Criteria: 1. Diagnosis of hairy cell leukemia. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed as single‑agent therapy. 5. Disease is relapsed or refractory. 6. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 7. Request does not exceed health plan‑approved quantity limit, if applicable. 8. Dose is within FDA maximum limit for any FDA‑approved indication or is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 9. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial: Primary CNS Lymphoma (Off‑Label)

Covered when ALL of the following are met:

Primary CNS Lymphoma Off‑Label Criteria: 1. Diagnosis of central nervous system (CNS) lymphoma. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Prescribed with autologous stem cell reinfusion in one of the following ways: a) as single‑agent therapy; b) in combination with high‑dose cytarabine. 5. Disease is relapsed or refractory. 6. Member has received prior whole brain radiation therapy or a methotrexate‑based regimen without prior radiation therapy. 7. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 8. Request does not exceed health plan‑approved quantity limit, if applicable. 9. Dose is within FDA maximum limit for any FDA‑approved indication or is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 10. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Continuation/Renewal Criteria

Covered when ALL of the following are met:

Continuation Criteria: 1. Member is currently receiving Brukinsa via the Centene benefit, or documentation supports current receipt of Brukinsa for a covered indication for ≥ 30 days. 2. Member is responding positively to therapy. 3. For brand Brukinsa requests, member must use generic zanubrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 4. Request does not exceed health plan‑approved quantity limit, if applicable. 5. If request is for a dose increase, the new dose must meet one of the following: a) new dose does not exceed 320 mg per day; b) if co‑administered with a moderate CYP3A4 inducer, new dose does not exceed 640 mg per day; c) new dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence). 6. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Approved and Supported Regimens

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib + obinutuzumab (Gazyva)	Follicular lymphoma: relapsed, refractory, or progressive disease; member has received ≥2 prior lines of systemic therapy; prescribed by or in consultation with an oncologist or hematologist; age ≥ 18 years; dose within plan limits (≤320 mg/day or ≤640 mg/day if co‑administered with a moderate CYP3A4 inducer) or supported by guidelines/literature.	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib as single agent; Zanubrutinib + Tevimbra (for Richter transformation); Zanubrutinib + venetoclax (Venclexta)	Chronic lymphocytic leukemia / SLL: diagnosis of CLL/SLL; prescribed by/with oncologist or hematologist; age ≥ 18 years; options include single agent, combination with Tevimbra for histologic (Richter) transformation to DLBCL, or combination with venetoclax; if BTK C481S mutation positive, member must not have had previous disease progression on Imbruvica; dose within plan limits (≤320 mg/day; ≤640 mg/day with moderate CYP3A4 inducer) or supported by guidelines/literature.	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib monotherapy; Zanubrutinib + rituximab; Zanubrutinib as component of TRIANGLE regimen; combinations with obinutuzumab (Gazyva) and venetoclax (Venclexta) per updates	Mantle cell lymphoma: diagnosis of MCL; prescribed by/with oncologist or hematologist; age ≥ 18 years; options include single agent (with ≥1 prior therapy for that option), combination with rituximab, combination with Gazyva and venetoclax, or as component of TRIANGLE regimen; use generic when available; if BTK C481S mutation positive, member must not have had previous disease progression on Imbruvica; dose within plan limits (≤320 mg/day; ≤640 mg/day with moderate CYP3A4 inducer) or supported by guidelines/literature.	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib single agent; Zanubrutinib in combination with rituximab	Waldenström's macroglobulinemia / lymphoplasmacytic lymphoma: diagnosis of WM or LPL; prescribed by/with oncologist or hematologist; age ≥ 18 years; prescribed as single agent or in combination with rituximab; for brand requests, use generic zanubrutinib if available; Brukinsa not prescribed concurrently with Calquence (per references); dose within plan limits (≤320 mg/day; ≤640 mg/day with moderate CYP3A4 inducer) or supported by guidelines/literature.	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib monotherapy or in combination (e.g., with venetoclax or Tevimbra for Richter transformation)	Chronic lymphocytic leukemia / SLL per NCCN: diagnosis of CLL/SLL; prescribed by/with oncologist or hematologist; age ≥ 18 years; monotherapy or combination per NCCN including combinations with venetoclax or with Tevimbra for Richter transformation; if BTK C481S mutation positive, member must not have had previous disease progression on Imbruvica; dose within plan limits (≤320 mg/day; ≤640 mg/day with moderate CYP3A4 inducer) or supported by guidelines/literature.	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib monotherapy	Marginal zone lymphoma (MZL): diagnosis of specified MZL subtype; prescribed by/with oncologist or hematologist; age ≥ 18 years; prescribed as single agent for relapsed, refractory, or progressive disease; member has received ≥1 line of systemic therapy including an anti‑CD20 agent (e.g., rituximab); dose within plan limits (≤320 mg/day; ≤640 mg/day with moderate CYP3A4 inducer) or supported by guidelines/literature.	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib monotherapy	Hairy cell leukemia (off‑label per NCCN): diagnosis of hairy cell leukemia; prescribed by/with oncologist or hematologist; age ≥ 18 years; prescribed as single agent for relapsed or refractory disease; dose within FDA maximum limit for any FDA‑approved indication or supported by guidelines/literature (prescriber submit evidence).	Covered

Regimen	Indication / Key Criteria	Coverage
Zanubrutinib as single agent with autologous stem cell reinfusion or in combination with high‑dose cytarabine	Primary central nervous system (CNS) lymphoma (off‑label per NCCN): diagnosis of CNS lymphoma; prescribed by/with oncologist or hematologist; age ≥ 18 years; prescribed with autologous stem cell reinfusion as single agent or in combination with high‑dose cytarabine; disease is relapsed or refractory; member has received prior whole brain radiation therapy or methotrexate‑based regimen without prior radiation; request does not exceed health plan‑approved quantity limit; dose within FDA maximum limit or supported by guidelines/literature.	Experimental

Provider Actions and Prior Authorization Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required before medication initiation. The prescriber must certify diagnosis, specialty (oncologist or hematologist where specified), age, regimen details, prior lines of therapy when applicable, and that brand requests meet generic-first requirements unless contraindicated or intolerant.

Prior authorization required for all indications listed under Initial Approval Criteria.
Prescriber specialty and regimen specifics must be documented for applicable diagnoses (e.g., MCL, MZL).

Documentation Required

Documentation Requirement

Provider must submit supporting clinical documentation (office chart notes, lab results, prior treatment records, and other relevant clinical information) demonstrating the member meets all approval criteria. Failure to submit required documentation may result in denial or delay of the request.

Include documentation of diagnosis, prescriber consultation/ specialty, prior therapies and dates, and rationale for dose or off‑label use when applicable.
If requesting branded product when generic zanubrutinib is available, include documentation of contraindication or intolerance to generic formulation.

Denial Risk

Requests for Non‑FDA Indications

Requests for non‑FDA approved indications (off‑label uses) may be considered only with sufficient supporting evidence of efficacy and safety per the off‑label use policies for the applicable line of business. If the requested use is not addressed in this policy and criterion for label-change handling does not apply, refer to the off‑label use policies listed.

Commercial: CP.CPA.09
Health Insurance Marketplace: HIM.PA.154
Medicaid: CP.PMN.53

Note

Handling Recent Label Changes

If the drug has undergone a recent label change (within the last 6 months) not yet reflected in this policy (new indication, age expansion, dosing change), providers should follow the plan's formulary/non‑formulary or no‑coverage guidance until the policy is updated. Refer to the appropriate formulary or non‑formulary policy for the member's line of business.

Formulary/drug list guidance: CP.CPA.190 (commercial), HIM.PA.33 (marketplace), CP.PMN.255 (Medicaid).
Non‑formulary guidance: CP.CPA.190 (commercial), HIM.PA.103 (marketplace), CP.PMN.16 (Medicaid).

Step Therapy

Prior Therapy Requirements

Prior therapy requirements apply for specified indications. For example, MCL requires ≥1 prior therapy when used as single‑agent therapy (see Appendix B) and MZL requires ≥1 prior line of systemic therapy including an anti‑CD20 agent (e.g., rituximab) prior to approval. Providers must document prior lines of therapy, regimens used, and outcomes (refractory, relapsed, progressive) as applicable.

Document prior systemic therapies and specify whether an anti‑CD20 (rituximab or biosimilar) was received for MZL.
Prior authorization may be required for some prior therapies per Appendix B.

Dosing and Coding Details

inv-11: Maximum daily dose — 320 mg/day normal; 640 mg/day if co‑administered with moderate CYP3A4 inducer

Maximum daily dose (standard)320 mg/day (4 capsules or 2 tablets)

Maximum daily dose (with moderate CYP3A4 inducer)640 mg/day (8 capsules or 4 tablets) — e.g., with bosentan, efavirenz, phenobarbital, primidone

Dose documentation requirementDose exceeding these limits must be supported by practice guidelines or peer‑reviewed literature with prescriber submission of evidence

inv-12: Dose — typical regimens 160 mg PO BID or 320 mg PO QD; Maximum dose details including CYP3A4 inducer adjustment

Typical dosing regimens160 mg orally twice daily (160 mg PO BID) or 320 mg orally once daily (320 mg PO QD)

Maximum dose (standard)Do not exceed 320 mg/day (4 capsules or 2 tablets)

Maximum dose with moderate CYP3A4 inducerIf co‑administered with a moderate CYP3A4 inducer, do not exceed 640 mg/day (8 capsules or 4 tablets)

Support for off‑label dosingAny dose outside these limits must be supported by practice guidelines or peer‑reviewed literature; prescriber must submit supporting evidence

Biomarker and Mutation Requirements

inv-29: BTK C481S mutation — if positive, member must not have had previous disease progression on ibrutinib (Imbruvica) for some indications

BTK C481S mutation — coverage implicationIf tumor is positive for BTK C481S mutation, member must not have had previous disease progression on ibrutinib (Imbruvica) for specified indications (e.g., MCL, CLL/SLL)

Applies to which indicationsRequirement noted specifically in MCL and CLL/SLL criteria per NCCN and policy updates

DocumentationMutation status and prior clinical course (including prior progression on Imbruvica) should be documented in the request

inv-30: BTK C481S — positive for BTK C481S mutation with historical note about Imbruvica progression

BTK C481S — interpretationPositive for BTK C481S mutation requires that the member has not had previous disease progression on Imbruvica for the relevant indications (historical note per NCCN and policy updates)

Historical policy changePolicy clarified in updates that if BTK C481S is present, prior progression on Imbruvica must not have occurred for MCL and CLL/SLL

Prescriber actionInclude mutation test result and prior treatment response history in prior authorization documentation

Definitions and Abbreviations

inv-22: Zanubrutinib (Brukinsa) — BTK inhibitor definition/key drug identifier

Drug name (brand)Zanubrutinib (Brukinsa)

MechanismBruton tyrosine kinase (BTK) inhibitor (oral targeted therapy for B‑cell malignancies)

Common indications (per FDA)MCL, WM, relapsed/refractory MZL, CLL/SLL, relapsed/refractory FL (with obinutuzumab) — see policy for indication‑specific criteria

inv-23: Bruton tyrosine kinase — BTK abbreviation/definition

AbbreviationBTK

DefinitionBruton tyrosine kinase — a kinase targeted by agents such as zanubrutinib for B‑cell malignancies

Context in policyListed in Appendix A: abbreviation/acronym key and used throughout indication criteria

inv-24: chronic lymphocytic leukemia — CLL abbreviation/definition

AbbreviationCLL

Definitionchronic lymphocytic leukemia — included as an FDA‑approved indication for zanubrutinib (Brukinsa)

Related termSLL — small lymphocytic lymphoma, grouped with CLL in policy criteria

inv-25: mantle cell lymphoma — MCL abbreviation/definition

AbbreviationMCL

Definitionmantle cell lymphoma — an FDA‑approved indication for zanubrutinib (Brukinsa); policy includes indication‑specific criteria

Line of therapy notePolicy notes MCL approval for patients who have received at least one prior therapy (see FDA indication and coverage criteria)

inv-26: Waldenström's macroglobulinemia — WM abbreviation/definition

AbbreviationWM

DefinitionWaldenström's macroglobulinemia — an FDA‑approved indication for zanubrutinib (Brukinsa)

Related entityLPL — lymphoplasmacytic lymphoma is referenced as off‑label in the policy and addressed under WM criteria

OpenPayer

Clinical Policy: Zanubrutinib (Brukinsa)

Coverage Criteria for Zanubrutinib (Brukinsa)

Approved and Supported Regimens

Provider Actions and Prior Authorization Requirements

Dosing and Coding Details

Line of Therapy Considerations

Biomarker and Mutation Requirements

Definitions and Abbreviations

Background

Policy Revision History