CurrentBlue Cross Blue Shield - IowaPolicy N/A

Hereditary angioedema (HAE) therapies — drug coverage criteria

Defines medical necessity, prior authorization documentation, and coverage criteria for HAE therapies for Wellmark/Blue Cross and Blue Shield members; affects prescribing clinicians and prior authorization reviewers.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyHereditary angioedema (HAE) therapies — drug coverage criteria

Policy CodePolicy N/A

Change TypeNo material change

Effective DateN/A

Next Review DateN/A

Key ActionSubmit required laboratory and clinical documentation with prior authorization; medication should be prescribed by or in consultation with an HAE specialist when applicable.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Ruconestpreferred product for acute HAE attacks

12 monthstypical authorization duration

≥50%reduction in attack frequency required

8Ekterly quantity limit

20Haegarda vial limit

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Coverage Criteria for HAE Therapies

Initial approval — Andembry

Criteria for Initial Approval

ALL of the following

I. Andembry may be considered medically necessary for the prevention of HAE attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- ALL of the following
  - C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
  - Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).
OR
ANY of the following
- Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
- Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
- Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

Treatment of acute HAE attacks — Berinert

Approval will be for 12 months.

ALL of the following

II. Berinert may be considered medically necessary for the treatment of HAE attacks when the requested medication will not be used with Ekterly, Firazyr/Sajazir, Kalbitor, or Ruconest and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member must meet at least one of the following exception criteria:
- Member is currently receiving treatment with Berinert through health insurance (not obtained as samples or via manufacturer's patient assistance programs).
- Member has tried and experienced an inadequate response to Ruconest.

Initial approval — Cinryze

Approval will be for 30 days.

ALL of the following

IV. Cinryze may be considered medically necessary for the prevention of HAE attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

Initial approval — Dawnzera

Approval will be for 12 months.

ALL of the following

V. Dawnzera may be considered medically necessary for the prevention of HAE attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

Treatment of acute HAE attacks — Firazyr/Sajazir

Approval will be for 12 months.

ALL of the following

VII. Brand and generic Firazyr/Sajazir (icatibant) may be considered medically necessary for the treatment of acute HAE attacks when the requested medication will not be used in combination with Berinert, Ekterly, Kalbitor, or Ruconest and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has a C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

COVERAGE CRITERIA — Ekterly (acute HAE attacks)

Approval will be for 12 months.

ALL of the following

VI. Ekterly may be considered medically necessary for the treatment of HAE attacks when the requested medication will not be used with Berinert, Firazyr/Sajazir, Kalbitor, or Ruconest and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member must meet at least one of the following exception criteria:
- Member is currently receiving treatment with Ekterly through health insurance (not obtained as samples or via manufacturer's patient assistance programs).
- Member has tried and experienced an inadequate response to Firazyr/Sajazir (icatibant).

COVERAGE CRITERIA — Haegarda (prophylaxis)

Approval will be for 12 months.

ALL of the following

VIII. Haegarda may be considered medically necessary for the prevention of HAE attacks when the requested medication will not be used in combination with any other medication used for prophylaxis of HAE attacks and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

COVERAGE CRITERIA — Kalbitor (acute HAE attacks)

Approval will be for 12 months.

ALL of the following

IX. Kalbitor may be considered medically necessary for the treatment of acute HAE attacks when the requested medication will not be used in combination with Berinert, Ekterly, Firazyr/Sajazir, and Ruconest and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has a C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

COVERAGE CRITERIA — Ruconest (acute HAE attacks)

Approval will be for 12 months.

ALL of the following

XI. Ruconest may be considered medically necessary for the treatment of acute HAE attacks when the requested medication will not be used in combination with Berinert, Ekterly, Firazyr/Sajazir, or Kalbitor and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has a C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

COVERAGE CRITERIA — Orladeyo and Takhzyro (prophylaxis)

Approval will be for 12 months.

ALL of the following

X. Orladeyo may be considered medically necessary for prevention of hereditary angioedema attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met at the time of diagnosis:
ANY of the following
- Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
- C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
- Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

Continuation of therapy — acute treatments

Continuation of Therapy

ALL of the following

I. Authorization of 12 months may be granted for continuation of therapy of Berinert, Ekterly, Kalbitor, Firazyr/Sajazir, and Ruconest for the treatment of acute HAE attacks when all of the following criteria are met:
ALL of the following
- Member meets the criteria for initial approval.
- Member has experienced reduction in severity and/or duration of acute attacks.
- Prophylaxis should be considered based on the attack frequency, attack severity, comorbid conditions, and member's quality of life.

Initial Therapy Criteria by Agent

Initial therapy — prophylactic agents

Initial therapy common criteria: Requested prophylactic medication will not be used in combination with any other prophylactic HAE medication AND patient has either C1-INH deficiency/dysfunction confirmed by laboratory testing (C1-INH antigenic level below laboratory lower limit OR normal antigenic level with low functional C1-INH [functional <50% or below laboratory lower limit]) OR normal C1-INH with a pathogenic gene mutation (F12, ANGPT1, PLG, KNG1, HS3ST6, MYOF) OR documented family history with angioedema refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg/day or equivalent for ≥1 month)

Used across listed prophylactic agents; approval duration typically 12 months

Initial therapy criteria (per-agent logic)

General initial requirement: Requested HAE medication will not be used in prohibited combination with listed other HAE agents AND member meets either laboratory evidence of C1-INH deficiency/dysfunction OR specified genetic mutation or documented family history with refractory angioedema to high-dose antihistamine; agent-specific exception criteria apply for Ekterly and Berinert as described in per-agent sections

Continuation of Therapy Requirements

Continuation of therapy

Continuation documentation: Chart notes demonstrating reduction in frequency for prophylactic agents (Andembry, Cinryze, Dawnzera, Haegarda, Orladeyo, Takhzyro) OR reduction in severity and/or duration for acute agents (Berinert, Ekterly, Firazyr/Sajazir/icatibant, Kalbitor, Ruconest)

Authorization of 12 months typical when continuation criteria met

Continuation of therapy rules for multiple agents

Berinert/Ekterly/Kalbitor/Firazyr/Sajazir/Ruconest continuation: Member meets initial approval criteria AND has experienced reduction in severity and/or duration of acute attacksAuthorization of 12 months

Step Therapy and Exceptions

Step	Requirement	Exceptions / Notes
1
Berinert generally requires trial/failure, intolerance, or contraindication to the preferred product Ruconest before approval.
Ruconest is the preferred product for treatment of acute HAE attacks; exceptions permitting Berinert include: age <13 years, current treatment with Berinert through insurance, inadequate response or intolerable adverse event to Ruconest, contraindication to Ruconest (e.g., known or suspected rabbit allergy), or request for laryngeal attack treatment.

Documentation Requirement	Details / Acceptable Evidence	Reviewer Action
Documentation of prior treatment failure or adverse events to formulary alternatives
Chart notes or other documentation must indicate prior treatment failure, severity of adverse event (if any), and dosage and duration of prior treatment; for non‑formulary exceptions, prescribed dose/quantity must fall within FDA labeling or compendia guidelines.
Verify chart notes include medication name(s), dates, dose, duration, reason for discontinuation (lack of efficacy or adverse event) and supporting diagnostic/lab results when applicable.

Quantity Limits for HAE Therapies

Prior Authorization

Provider actions / notes

Requests exceeding the stated quantity limits may be denied. Prior authorization is required for HAE therapies; benefits and exclusions should be verified before submission. For prior authorization, include documentation of diagnosis, prior medications/trials (including any Ekterly exception or step therapy notes), and prescriber specialty as applicable. Approvals are typically issued for up to 12 months. Ensure benefit verification and check for member-specific exclusions; required documentation for prior authorization must be provided to avoid delays.

Prior Authorization and prescriber specialty: Prior authorization required; include prescriber specialty when applicable.
Prior authorization — 12 month approvals: Authorizations may be approved for up to 12 months.
Benefit verification and exclusions: Verify member benefits and exclusions prior to claim submission.
Quantity limit exceedance: Requests exceeding stated quantity limits may be denied.
Required documentation for prior authorization: Include diagnosis, prior therapy history, clinical rationale, and any Ekterly exception/step requirement documentation.
Ekterly exception/step requirement: Note any step-therapy exceptions or documented failure/intolerance to required agents when requesting Ekterly.

Procedures, Billing Codes, and Key Coding Rules

Procedures and billing codesHCPCS

J0593	Injection, lanadelumab-flyo, Takhzyro, 1 mg
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, Kalbitor, 1 mg
J1744	Injection, icatibant, 1 mg

Procedures/Billing J-codesHCPCS

J0593	Injection, lanadelumab-flyo, Takhzyro, 1 mg
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, Kalbitor, 1 mg
J1744	Injection, icatibant, 1 mg

Significant reduction in attack frequency (threshold for some continuation approvals)

Threshold≥ 50% reduction in attack frequency

ContextUsed for continuation approval of prophylactic agents (e.g., Andembry, Cinryze, Haegarda, Orladeyo, Dawnzera, Takhzyro)

DocumentationChart notes must demonstrate reduction in frequency and reduced use of acute medications

Haegarda vial limit (key value)

Limit20 vials per 30 days

Applies toHaegarda 2000 IU and 3000 IU vials

Prior Authorization, Documentation, and Billing Guidance

Prior Authorization

Prior authorization — submit required documentation and specialty prescriber

Submit a prior authorization request with the required laboratory and clinical documentation, and ensure the medication is prescribed by or in consultation with a prescriber who specializes in HAE management.

Include initial-authorization labs (C1-INH functional and antigenic levels) and any applicable genetic testing.
Prescriber must specialize in management of HAE or be in consultation with such a specialist.

Prior Authorization

Prior authorization — 12-month approvals when criteria met

When the drug-specific medical necessity criteria are met, prior authorization may be approved for a 12-month period for most agents.

Approval duration of 12 months is noted for multiple agents (e.g., Andembry, Haegarda, Ruconest, Orladeyo, Takhzyro, Ekterly).

Site of Care and Infusion Guidance

Note

Infusion center approvals — subject to dosing limits

Approvals for infused therapies may be subject to dosing limits consistent with FDA labeling, compendia, and evidence‑based guidelines; the policy does not explicitly restrict site of care to or from infusion centers.

Ensure dosing requested aligns with FDA‑approved labeling and accepted compendia to avoid approval limits.

Billing Rule

Infusion center billing — use facility and HCPCS codes

When services are provided in an infusion center, bill using appropriate facility revenue codes and HCPCS J‑codes as listed; the policy does not give explicit site‑of‑care restrictions.

Use the policy's listed J‑codes and applicable facility/revenue codes when submitting claims from an infusion center.
Confirm billing under the correct benefit (medical vs pharmacy) per member coverage.

Definitions and Diagnostic Criteria

HAE therapies (definition key)

DefinitionTherapies that inhibit formation or activity of bradykinin used to prevent or treat hereditary angioedema

ExamplesAndembry, Berinert, Cinryze, Haegarda, Dawnzera, Firazyr/Sajazir, Ekterly, Kalbitor, Orladeyo, Takhzyro, Ruconest

Routes of administrationOral (Ekterly, Orladeyo), IV (Ruconest, Berinert, Cinryze), SC (Andembry, Dawnzera, Firazyr/Sajazir, Haegarda, Kalbitor, Takhzyro)

C1-INH deficiency/dysfunction — laboratory documentation

Laboratory documentationC1‑INH antigenic level below the laboratory lower limit of normal OR normal antigenic level with low functional C1‑INH (<50% or below lab lower limit)

When required

Background on Hereditary Angioedema

Hereditary angioedema (HAE) results from excessive formation or activity of bradykinin due to deficiency or dysfunction of the C1 esterase inhibitor (C1‑INH). This increased bradykinin activity produces capillary leakage and localized swelling. Therapies included in this policy act at different points in the bradykinin pathway — for example, replacement or recombinant C1‑INH (intravenous), kallikrein inhibitors and monoclonal antibodies (subcutaneous), bradykinin B2 receptor antagonists (subcutaneous), and oral agents — with the shared goal of reducing formation or effects of bradykinin to prevent or treat HAE attacks.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyHereditary angioedema (HAE) therapies — drug coverage criteria

Policy CodePolicy N/A

Change TypeNo material change

Effective DateN/A

Next Review DateN/A

Key ActionSubmit required laboratory and clinical documentation with prior authorization; medication should be prescribed by or in consultation with an HAE specialist when applicable.

SourceLink

On This Page

Member has tried and experienced an intolerable adverse event to Ruconest.

Member has a contraindication to Ruconest (e.g., known or suspected allergy to rabbits or rabbit-derived products).

Member is less than 13 years of age.

Berinert is being requested for treatment of laryngeal attacks.

ANY of the following

Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

ANY of the following

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

ANY of the following

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

ANY of the following

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

Member has tried and experienced an intolerable adverse event to Firazyr/Sajazir (icatibant).

Member has a contraindication to Firazyr/Sajazir (icatibant).

Member is less than 18 years of age.

ANY of the following

Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

ANY of the following

Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

ANY of the following

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

ANY of the following

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

ANY of the following

Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
Member has an F12, angiopoietin-1, plasminogen, kininogen-1 (KNG1), heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6), or myoferlin (MYOF) gene mutation as confirmed by genetic testing.
Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine 40 mg per day or equivalent) for at least one month.

XII. Takhzyro may be considered medically necessary for the prevention of HAE attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met at the time of diagnosis:

ANY of the following

Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets one of the following criteria:
C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test.
Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test).

II. Authorization may be granted for continuation of therapy of Berinert for short-term preprocedural prophylaxis (i.e., prior to surgical or major dental procedures) when all initial authorization criteria are met.

III. Authorization of 12 months may be granted for continuation of therapy of Andembry, Cinryze, Haegarda, and Orladeyo when all of the following criteria are met:

ALL of the following

Member meets the criteria for initial approval.
Member has experienced a significant reduction in frequency of attacks (e.g., ≥ 50%) since starting prophylactic treatment.
Member has reduced the use of medications to treat acute attacks since starting prophylactic treatment.

IV. Authorization of 12 months may be granted for continuation of therapy of Dawnzera when all of the following criteria are met:

ALL of the following

Member meets the criteria for initial approval.
Member has experienced a significant reduction in frequency of attacks (e.g., ≥ 50%) since starting treatment.
Member has reduced the use of medications to treat acute attacks.

The requested drug is being dosed every 8 weeks or dosing every 8 weeks has been considered if the member is well-controlled on therapy for 6 months.

V. Authorization of 12 months may be granted for continuation of therapy of Takhzyro when all of the following criteria are met:

ALL of the following

Member meets the criteria for initial approval.
Member has experienced a significant reduction in frequency of attacks (e.g., ≥ 50%) since starting treatment.
Member has reduced the use of medications to treat acute attacks.
The requested drug is being dosed every 4 weeks or dosing every 4 weeks has been considered if the member is well-controlled on therapy for 6 months.

Requests for the continuation of therapy of Andembry, Berinert, Cinryze, Dawnzera, Ekterly, Brand and generic Firazyr/Sajazir, Haegarda, Kalbitor, Orladeyo, Ruconest, and Takhzyro are considered not medically necessary for patients who do not meet the criteria set forth above.

Approval duration typically 12 months for most agents

Berinert short-term preprocedural prophylaxis: Member meets initial authorization criteria

Andembry/Cinryze/Haegarda/Orladeyo continuation: Member meets initial approval criteria AND has experienced ≥50% reduction in attack frequency AND reduced use of medications for acute attacksAuthorization of 12 months

Dawnzera continuation: Member meets initial approval criteria AND has experienced ≥50% reduction in frequency AND reduced use of medications to treat acute attacksAuthorization of 12 months

Takhzyro continuation: Member meets initial approval criteria AND has experienced ≥50% reduction in frequency AND reduced use of medications to treat acute attacks AND the requested drug is being dosed every 4 weeks (or every 4 weeks has been considered if member well-controlled for 6 months)Authorization of 12 months

Dosing every 8 weeks may be considered if well-controlled for 6 months

ContextQuantity limit for prophylactic Haegarda supply; approval typically 12 months when criteria met

Billing Rule

Prior authorization implied; billing uses listed J‑codes

Prior authorization is implied for specialty HAE drugs subject to the payer's pharmacy benefit and quantity limits; when billing infused or injected therapies, use the policy's listed J‑codes.

Billing should use the appropriate HCPCS J‑codes listed in the policy (e.g., J0596, J0597, J0598, J0599, J0593, J1290, J1744).
Confirm whether the drug is covered under the pharmacy or medical benefit and adhere to applicable quantity limits.

Step Therapy

Preferred agent (Ruconest) and Berinert exception requirements

The policy steers acute-attack treatment toward Ruconest as the preferred agent; use of Berinert generally requires meeting exception criteria such as trial/failure, intolerance, contraindication to Ruconest, age-based exceptions, or current coverage.

Ruconest is the preferred product for treatment of acute HAE attacks.
Berinert requires at least one exception: current Berinert coverage, inadequate response to Ruconest, intolerable adverse event to Ruconest, contraindication to Ruconest (e.g., rabbit allergy), age <13, or laryngeal attack.

Step Therapy

Ekterly — exception/step requirement

Ekterly approval requires that the member meet at least one exception criterion before approval, such as current insurance coverage, prior inadequate response/intolerance/contraindication to icatibant, or age <18.

Document which exception criterion is met (e.g., prior inadequate response to icatibant).

Documentation Required

Required documentation — labs and genetic testing

For initial prior authorization, include C1‑INH functional and antigenic protein levels and relevant genetic testing (F12, ANGPT1, PLG, KNG1, HS3ST6, MYOF) when applicable; for continuation, provide chart notes demonstrating response (reduction in frequency for prophylaxis or reduction in severity/duration for acute agents).

Provide C1‑INH antigenic level and functional level test results.
Include genetic testing results if applicable and chart notes confirming family history or prior antihistamine trial when relevant.

Documentation Required

Required documentation — rule out other causes of angioedema

Document diagnostic testing and clinical evaluation that rule out other causes of angioedema (e.g., ACE‑I induced, estrogen-related, allergic) when applicable as part of the authorization.

Include diagnostic testing/lab results as appropriate.
Document that alternative causes of angioedema have been considered and ruled out.

Billing Rule

Billing documentation — report services with appropriate codes

When billing for infused or injected HAE therapies, report services using appropriate CPT, HCPCS (policy-listed J‑codes), revenue, and ICD diagnostic codes.

Use the HCPCS J‑codes listed in the policy (e.g., J0596 Ruconest, J0597 Berinert, J0598 Cinryze, J0599 Haegarda, J0593 Takhzyro, J1290 Kalbitor, J1744 icatibant).

Note

Verify benefits and exclusions before requesting authorization

Verify individual member benefits, exclusions, limitations, or exceptions prior to authorization; Wellmark determines medical necessity only if the benefit exists and no contract exclusions apply.

Confirm member-specific coverage and whether the policy applies to the member's contract (FEP or other exclusions may affect applicability).

Denial Risk

Not medically necessary if policy criteria are not met

Requests for the listed HAE drugs are considered not medically necessary and may be denied when the patient does not meet the specific policy criteria for that product.

Affected products include Andembry, Berinert, Cinryze, Dawnzera, Ekterly, Firazyr/Sajazir (brand and generic), Haegarda, Kalbitor, Orladeyo, Ruconest, and Takhzyro.

Required for initial authorization of many HAE therapies and for acute treatment agents (e.g., Firazyr/Sajazir, Berinert, Ruconest)

Source wording'C1 inhibitor (C1‑INH) antigenic level below the lower limit of normal… or Normal C1‑INH antigenic level and a low C1‑INH functional level (functional C1‑INH less than 50% or ...)'

Normal C1-INH with HAE-related gene mutation or refractory family history — qualifying criteria

Qualifying criteriaNormal C1‑INH by laboratory testing plus either a pathogenic mutation (F12, ANGPT1, PLG, KNG1, HS3ST6, or MYOF) confirmed by genetic testing OR documented family history of angioedema refractory to high‑dose antihistamine (cetirizine 40 mg/day or equivalent for ≥1 month)

Applies toPatients with normal C1‑INH who otherwise meet genetic or family‑history criteria for HAE

Documentation neededGenetic testing results or chart documentation of family history and prior high‑dose antihistamine trial

HAE references and guidelines

Primary sourcesProduct package inserts (Andembry, Berinert, Cinryze, Dawnzera, Ekterly, Firazyr/Sajazir, Kalbitor, Ruconest, Haegarda, Takhzyro, Orladeyo)

Clinical guidelinesWAO/EAACI 2021 guideline, US HAEA 2020 guidelines, international consensus documents and other referenced consensus reports

Use in policyReferences and guidelines underpin diagnostic definitions, indication determinations, and continuation criteria in the policy