Hereditary Angioedema Agents
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Clinical coverage and prior authorization criteria for medical-benefit hereditary angioedema (HAE) drugs for prophylaxis and treatment, including age limits, diagnostic verification, approval durations, and quantity limits. Affects providers prescribing or requesting authorization for HAE agents for Anthem members.
Added new agent Dawnzera to clinical criteria and quantity limits and added HCPCS NOC J3490 and C9399 for Dawnzera.
Added new agent Andembry to clinical criteria and quantity limits and corresponding HCPCS NOC codes.
Step therapy tables updated multiple times (03/01/2026, 02/01/2026, 12/01/2025).
Coverage and Medical Necessity Criteria
Exclusions and Not Medically Necessary Conditions
Not covered / may be denied when ANY of the following apply:
Acute Attack Agents - quantity limits
Covered for acute treatment when provided within per-attack and per-period quantity limits
Combination use of hereditary angioedema (HAE) agents for the same purpose is not approved. Specifically, prophylactic agents (for example, Cinryze, Haegarda, Takhzyro, Andembry, Dawnzera, Orladeyo) should not be used concurrently for prophylaxis, and acute agents (for example, Berinert, Icatibant, Kalbitor, Ruconest) should not be used in combination for treatment of the same attack. In addition, certain agent-specific contraindications apply (for example, Dawnzera exclusions for hepatic impairment and Ruconest contraindication for rabbit allergy or use in laryngeal attacks).
This policy has an active document history with recent administrative and coding updates. Notable entries include the 09/08/2025 select review that added Dawnzera to the clinical criteria and HCPCS NOC coding, and the 08/15/2025 annual review that added Andembry and updated coding and documentation language. Earlier history documents prior step therapy and coding updates back to 2018.
Requests that do not meet the stated diagnostic, age, indication, or documentation requirements may be denied. Examples include lack of required laboratory confirmation (C4 below the laboratory lower limit plus C1‑INH antigenic or functional deficiency or known pathogenic C1‑INH mutation), patient age outside the agent-specific limits, use for an indication other than specified prophylaxis or acute treatment, or combination use of multiple HAE agents for the same purpose.
Coding listed in this document is provided for informational purposes only. Inclusion or exclusion of a HCPCS or ICD code does not by itself determine coverage or reimbursement; actual coverage depends on the member’s contract benefits in effect at the time of service.
HCPCS / ICD-10 / Quantity Coding and Limits
| C9399 | Unclassified drugs or biologicals [when specified as Andembry (garadacimab-gxii) or Dawnzera (donidalorsen)] |
| J0593 | Injection, lanadelumab-flyo, 1 mg (code may be used for Medicare when drug administered under direct supervision of a physician, not for use when drug is self-administered) [Takhzyro] |
| J0596 | Injection, C-1 esterase inhibitor (recombinant), Ruconest, 10 units |
| J0597 | Injection, C-1 esterase inhibitor (human), Berinert, 10 units |
| J0598 | Injection, C-1 esterase inhibitor (human), Cinryze, 10 units |
| J0599 | Injection, c-1 esterase inhibitor (human), Haegarda, 10 units |
| J1290 | Injection, ecallantide, 1 mg [Kalbitor] |
| J1744 | Injection, icatibant, 1 mg [Firazyr] [Sajazir] |
| J3490 | Unclassified drugs [when specified as Dawnzera (donidalorsen)] |
| J3590 | Unclassified biologics [when specified as Andembry (garadacimab-gxii)] |
Prior Authorization, Documentation, and Denial Triggers
Prior authorization required — initial vs continuation requirements
Prior authorization is required for initial and continuation requests for HAE prophylaxis and for acute-attack agents. Initial requests must meet the initial criteria (diagnosis of HAE, prophylaxis indication, age appropriate for the requested drug, diagnostic verification with C4 and C1‑INH antigenic or functional level or known mutation, and history of moderate/severe attacks). Continuation requests must document diagnosis, prophylaxis indication, diagnostic verification at initiation of therapy, and a positive clinical response (clinically significant reduction in number or frequency of attacks).
- Initial authorization: see agent-specific initial criteria and age limits (Cinryze/Haegarda ≥6 y; Takhzyro ≥2 y; Andembry/Dawnzera ≥12 y).
- Continuation authorization: must show diagnostic testing at therapy initiation and clinical response (reduction in attacks).
PA tied to quantity limits and override provisions
Prior authorization is tied to the clinical criteria and to agent-specific quantity limits; approvals will follow the listed per-attack and per-period limits and override rules. Use the specified HCPCS/NOC codes when requesting authorization but note that PA decisions are based on clinical criteria and quantity rules, not just coding.
- Acute agent quantity limits (examples): Berinert up to 20 IU/kg once per attack (max 24 kits/30 days); Icatibant up to 3 syringes per attack (max 18/30 days); Ruconest up to two 50 U/kg doses per attack (max 16 vials/30 days).
- Prophylaxis dispensing limits (examples): Takhzyro 1 syringe per 28 days (override/titration rules allow 2 syringes/28 days during initial period); Dawnzera 1 autoinjector per 28 days; Cinryze 20 vials per 30 days.
- Override provisions (see Takhzyro initiation/titration and Andembry initiation allowances).
Step therapy — required trial or intolerance for non-preferred prophylaxis
For non-preferred prophylactic HAE agents, the member must have a documented trial or intolerance to one preferred agent, or documented anaphylaxis to ingredients in the preferred agent that are not present in the requested non-preferred agent.
- Acceptable reason to bypass step: trial/intolerance to one preferred agent, or documented anaphylaxis to preferred agent ingredients absent from requested agent.
Step therapy / formulary preference — benefit-type specific agents
Formulary preference varies by benefit type: Commercial benefit lists Haegarda and Takhzyro as preferred and Cinryze and Dawnzera as non-preferred (03/01/2026). Medicaid and other benefits list preferred/non-preferred agents by state and date; verify the member's benefit to confirm preferred status.
- Commercial (03/01/2026): Preferred = Haegarda, Takhzyro; Non-preferred = Cinryze, Dawnzera.
- Medicaid: preferred/non-preferred listings vary by state and effective date — check benefit-specific listings.
Required diagnostic laboratory verification (C4 and C1‑INH results)
Provide diagnostic laboratory verification with a C4 level below the laboratory lower limit of normal and at least one of: low C1‑INH antigenic level, low C1‑INH functional level, or a known HAE‑causing C1‑INH mutation. For continuation requests, documentation that these diagnostics were obtained at therapy initiation is required.
- C4 below lab lower limit PLUS one of: C1‑INH antigenic below lower limit, C1‑INH functional below lower limit, OR known HAE‑causing C1‑INH mutation.
- Continuation: verify that these tests were performed at therapy initiation and documented in the record.
Document attack severity and history to justify therapy
Document clinical severity and attack history to support prophylaxis or acute treatment: record history of moderate or severe attacks such as airway swelling, severe abdominal pain, facial swelling, nausea/vomiting, or painful facial distortion.
- Clinical history must describe attack severity and examples (airway swelling, severe abdominal pain, facial swelling, nausea/vomiting, painful facial distortion).
Documentation update — include referenced diagnostics and history
Administrative updates to the policy added documentation requirements; reference the document history for the effective dates of added documentation expectations (e.g., 08/15/2025 and 09/08/2025 entries). Ensure submitted records include the diagnostics and clinical history noted in the criteria.
- Document history entries note addition of Dawnzera and Andembry and an administrative update that added documentation requirements.
Denial triggers — common reasons requests are denied
Common denial reasons include missing diagnostic verification (C4 and C1‑INH results), therapy requested for the wrong indication (e.g., prophylaxis vs acute treatment mismatch), age outside the agent-specific limits, use in combination with other HAE agents for the same purpose, or documented contraindications/allergies.
- Missing or absent lab verification at initiation or on file.
- Request for an agent outside the approved indication (prophylaxis vs acute treatment).
- Age does not meet the agent-specific minimum.
- Use in combination with other HAE agents for same purpose.
Dawnzera hepatic impairment exclusion — NCI‑ODWG criteria
Dawnzera requests may be denied for individuals with moderate or severe hepatic impairment defined by NCI‑ODWG criteria (total bilirubin >1.5× ULN regardless of AST).
- If total bilirubin >1.5 times ULN (regardless of AST), Dawnzera is not approved.
Ruconest denials — laryngeal attacks and rabbit allergy
Ruconest is not approved for treatment of laryngeal attacks and may be denied for individuals with a known or suspected allergy to rabbits or rabbit‑derived products.
- Do not request Ruconest for laryngeal attacks; document absence of rabbit allergy before approval.
Coding does not guarantee coverage — verify member benefits
Inclusion or exclusion of procedure, diagnosis, or device codes in this policy is for informational purposes only and does not guarantee coverage or provider reimbursement; coverage decisions depend on the member's contract benefits in effect at time of service.
- Use listed HCPCS/NOC codes when applicable, but confirm member-specific coverage under their contract.
Background
Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent, bradykinin-mediated episodes of angioedema. Types I and II HAE are caused by deficiency or dysfunction of C1 inhibitor (C1‑INH), resulting in excessive bradykinin production. Clinical presentations include peripheral swelling, painful and severe abdominal attacks, and potentially life‑threatening laryngeal edema, with laryngeal involvement posing a risk of asphyxiation. Treatment strategies include plasma‑derived C1‑INH replacement and targeted therapies that inhibit kallikrein or reduce prekallikrein production; agent selection depends on indication (prophylaxis versus acute treatment), age, and safety considerations.
Definitions and Mechanisms
Document History and Changes
Step therapy table updated (document history notes step therapy table updates on 03/01/2026).
Step therapy table updated (document history notes step therapy table updates on 02/01/2026).
Step therapy table updated (document history notes step therapy table updates on 12/01/2025).
Select review added new agent Dawnzera to clinical criteria and quantity limits and added HCPCS NOC codes J3490 and C9399 for Dawnzera.
Annual review added new agent Andembry to clinical criteria and quantity limits, added HCPCS NOC C9399 and J3590 for Andembry, and included an administrative update to documentation requirements.
Annual review with wording and formatting changes; coding reviewed with no coding changes.
Annual review adjusted quantity limits for acute treatment agents icatibant (Firazyr, Sajazir) and Kalbitor; wording and formatting changes.
Select review updated Takhzyro age and added a new strength with quantity limits and override criteria for patients 6 years and older.
Step therapy table updated (document history lists a step therapy update on 03/27/2023).
Annual review added rabbit allergy to the MNA section for Ruconest.
Select review added Berinert Kit, removed Berinert Vial, and added branded generic Sajazir; coding updated to add Sajazir to HCPCS J1744.
Administrative update for Takhzyro and addition of 'do not approve' criteria in Acute Attacks Agents.
Select review updated Takhzyro quantity limits and added override criteria and updated approval duration limits for prophylaxis agents.
Select review updated Haegarda clinical criteria and prophylaxis step therapy for pediatric use, adding initial and continuation use criteria for prophylaxis agents.
Select review updated maximum quantity limits for acute attack agents Berinert, Firazyr, Ruconest, and Kalbitor.
Annual review discussed quantity limits for acute attack agents and updated coding effective 10/01/2019 (added HCPCS J0593; deleted J3490, J3590, C9399 effective 10/01/2019).
Updated non-preferred/step therapy listing to include Takhzyro as a potential preferred agent.
Annual review added new non-preferred step therapy for HAE prophylaxis, updated pediatric age criteria for Cinryze, and updated HCPCS/ICD-10 coding (J3590, C9399, D84.1); added J3490 with revised language.
Administrative updates in the document history include addition of new agents and related HCPCS/NOC coding. Specifically, the policy was updated on 09/08/2025 to add Dawnzera (donidalorsen) to clinical criteria and quantity limits and to add HCPCS NOC codes J3490 and C9399 for Dawnzera. The 08/15/2025 annual review added Andembry (garadacimab‑gxii) to clinical criteria and quantity limits and added HCPCS NOC codes C9399 and J3590.
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