ModifiedUnitedHealthcarePolicy CS2024D0044S

Hereditary Angioedema (HAE), Treatment and Prophylaxis

Defines UnitedHealthcare medical benefit drug coverage criteria for specific C1-esterase inhibitor and kallikrein-inhibitor products used to treat or prevent hereditary angioedema (HAE); applies to commercial medical benefit claims and prescribing providers. Affected products and clinical requirements for initial and continuation authorization are described.

Policy Summary

PayerUnitedHealthcare

PolicyHereditary Angioedema (HAE), Treatment and Prophylaxis

Policy CodePolicy CS2024D0044S

Change TypeCoverage criteria revisedgenetic and clinical eligibility updated

Effective DateDec 1, 2024

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of diagnosis (C1‑INH deficiency or qualifying genetic variant or HAE‑unknown) and specialist prescriber attestation.

SourceLink

POLICY UPDATE CHANGES

Revised coverage criteria for initial therapy for Berinert, Ruconest, Kalbitor, and Cinryze to add coverage when patients have recurring angioedema attacks refractory to high-dose antihistamines with unknown de-novo mutation(s) (HAE-unknown).

Replaced list of genetic mutations allowed for coverage to include confirmed presence of variants in genes for factor XII, angiopoietin-1, plasminogen-1, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase 6.

Updated Clinical Evidence and References sections to reflect most current information.

5drug products referenced under this policy window

4 codesHCPCS/NDC codes listed

12 moauthorization period

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.

Specialist-onlyprescriber restriction

12/01/2024revision effective

Coverage Criteria for HAE Therapies

Initial therapy (acute HAE attack) — Berinert, Ruconest, Kalbitor

Berinert, Ruconest, and Kalbitor are covered when ALL of the following are met for initial therapy (acute attack):

Initial therapy diagnosis: Diagnosis of hereditary angioedema (HAE) confirmed by either: (1) C1 inhibitor (C1-INH) deficiency or dysfunction (Type I or II) documented by C1-INH antigenic level below the lower limit of normal or C1-INH functional level below the lower limit of normal; OR (2) normal C1 inhibitor levels plus one of the following: confirmed presence of variant(s) in the gene(s) for factor XII, angiopoietin-1, plasminogen-1, kininogen-1, myoferlin, or HS3ST6; recurring angioedema attacks refractory to high-dose antihistamines with confirmed family history; OR recurring angioedema attacks refractory to high-dose antihistamines with unknown de-novo mutation(s) (HAE-unknown).

Use and combination restrictions: Used for treatment of an acute HAE attack and not used in combination with other approved treatments for acute HAE attacks (e.g., Berinert, Firazyr, Kalbitor, or Ruconest).

Prescriber requirement: Prescribed by an immunologist or allergist.

Administration attestation: For Berinert and Ruconest requests only: physician attestation that the patient is unable to self-administer or there is no competent caregiver to administer the drug.

Authorization duration: Initial authorization will be for no more than 12 months.

Continuation therapy (acute HAE attack)

Continuation (re-authorization) for acute therapy — covered when ALL of the following are met:

Clinical response: Documentation of positive clinical response.

Prescriber requirement: Prescribed by an immunologist or allergist.

Administration attestation: For Berinert and Ruconest requests only: physician attestation that the patient is unable to self-administer or there is no competent caregiver to administer the drug.

Cinryze — prophylaxis criteria

Cinryze is covered for prophylaxis when ALL of the following are met:

Diagnosis of HAE confirmed by either: C1-INH deficiency/dysfunction (antigenic or functional level below the lower limit of normal) or normal C1-INH with specified genetic variants or refractory recurrent angioedema as described in policy.

Intent of use: Used for prophylaxis against HAE attacks.

Combination restriction: Not used in combination with other products indicated for prophylaxis against HAE attacks (e.g., Haegarda, Takhzyro).

Prescriber requirement: Prescribed by an immunologist or allergist.

Administration attestation:

Guideline-based coverage criteria

Covered when meeting guideline-based indications

Acute attack treatment: Any HAE attack affecting or potentially affecting the upper airway or any attack recognized early should be considered for on-demand treatment with IV C1-INH, ecallantide, or icatibant.

Supported by WAO/EAACI and JTF practice parameters.

Prophylaxis: Long-term prophylaxis is appropriate for some patients to reduce frequency, duration, and severity of attacks; first-line options include plasma-derived C1-INH, lanadelumab, and berotralstat per guideline recommendations.

Use of androgens reserved as second-line; short-term prophylaxis recommended before procedures that can induce attacks.

Pediatric considerations: In pediatric patients consider tranexamic acid or antifibrinolytics when appropriate; plasma-derived C1-INH recommended when antifibrinolytics fail or are contraindicated; on-demand therapy should be available and training for home administration is recommended.

HAWK pediatric consensus guidance.

Ecallantide (Kalbitor) evidence

Covered acute therapy — ecallantide evidence

Ecallantide efficacy: Subcutaneous ecallantide 30 mg demonstrated rapid and significant symptom reduction versus placebo in randomized trials (EDEMA3/4), with benefits apparent within 2 hours and maintained to 24 hours; trials included patients aged ≥10 presenting within 8 hours of a moderate‑to‑severe attack.

C1-INH prophylaxis evidence

Covered prophylaxis — C1-INH (Cinryze) evidence

Cinryze prophylaxis: Prophylactic nanofiltered C1-INH (Cinryze) 1,000 units twice weekly is supported by randomized and open-label studies demonstrating significant reductions in attack rate, severity, and duration compared with placebo or historical rates.

Study populations included ages 3–82; twice-weekly dosing had superior response versus once-weekly.

Initial therapy (revised criteria)

Covered when ALL of the following are met for initial therapy with specified HAE agents (per revised policy):

Initial therapy criteria: Patient has recurrent angioedema attacks and meets one of the following: (1) confirmed presence of variant(s) in the gene(s) for factor XII, angiopoietin-1, plasminogen-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6; OR (2) recurring angioedema attacks refractory to high-dose antihistamines with unknown de-novo mutation(s) (HAE-unknown); OR (3) other standard indications per cited professional guidelines and FDA labeling for acute attacks or prophylaxis as applicable.

Revised initial therapy coverage conditions described in the policy.

Guideline-based treatment and prophylaxis stance

Coverage principles for treatment and prophylaxis per professional guidelines:

Treatment access: All patients with HAE should have access to at least one specific on-demand medicine (plasma-derived/recombinant C1-INH, icatibant, ecallantide); attacks should be treated early and any attack affecting or potentially affecting the airway should receive on-demand therapy.

HAWK and JTF guideline recommendations.

Prophylaxis indications: Long-term prophylaxis is appropriate when on-demand therapy is inadequate to reduce disease burden; plasma-derived C1-INH and other guideline-recommended agents can be considered as first-line options and prophylactic regimens individualized.

HAWK guidance.

Firazyr (icatibant), Haegarda (C1 esterase inhibitor, human), and Takhzyro (lanadelumab) are self‑administered injectable therapies and are dispensed under the member's pharmacy benefit. As such, coverage and benefit administration for these products are governed by the pharmacy benefit and not by the medical‑benefit criteria in this policy document.

Professional practice parameters note that epinephrine, corticosteroids, and antihistamines are not efficacious for treatment of hereditary angioedema (HAE) attacks and therefore are not recommended as HAE‑specific therapy.

Consistent with guideline updates, the use of epinephrine, corticosteroids, or antihistamines is explicitly stated as not recommended for HAE because available evidence does not demonstrate efficacy for HAE attacks.

Requests to use covered HAE therapies in combination with other approved acute or prophylactic HAE treatments are not consistent with the policy criteria. For example, acute agents should not be used in combination with other approved acute treatments (e.g., Berinert, Firazyr, Kalbitor, Ruconest), and prophylactic Cinryze should not be used in combination with other prophylactic products (e.g., Haegarda, Takhzyro). Such combination use would not meet coverage criteria.

Reinforcing guideline conclusions, the policy states that the use of epinephrine, corticosteroids, or antihistamines specifically to treat HAE is not supported by the evidence and therefore is not recommended as HAE‑specific therapy.

Coding and Dosing Information

Applicable HCPCS/J-codesHCPCS

J0596	Injection, C1 inhibitor (recombinant), Ruconest, 10 units
J0597	Injection, C1 esterase inhibitor (human), Berinert, 10 units
J0598	Injection, C1 esterase inhibitor (human), Cinryze, 10 units
J1290	Injection, ecallantide, 1 mg

Relevant ICD-10 Diagnosis CodesICD-10

D84.1

Defects in the complement system

Drugs referenced (informational)mixed

NDC/label references

Berinert, Cinryze, Kalbitor, Ruconest (FDA prescribing information cited)

inv-17: Berinert dosing used in trials

Trial doseBerinert 20 U/kg single IV dose (efficacy demonstrated in IMPACT studies)

Indication contextUsed for treatment of acute HAE attacks at any body location in trial populations

Study duration/contextEvaluated in long-term extension (median 24 months) treating successive attacks

inv-18: Ruconest trial dosing

Primary trial doseRuconest 50 U/kg IV (option for an additional 50 U/kg based on clinical response)

Response rate~90% of attacks treated with a single 50 U/kg dose in open-label study

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is expected for HAE therapies. Initial and reauthorization requests are limited to a maximum of 12 months. Providers should submit prior authorization requests to the payer and include the documentation described below to support medical necessity.

Initial and reauthorization approvals limited to no more than 12 months
Prior authorization required for Berinert, Ruconest, Kalbitor, Cinryze when used per policy

Denial Risk

Denial Risk — Diagnosis and Combination Use

Requests may be denied if the diagnosis of HAE is not confirmed according to the policy criteria, if required documentation is missing, or if the requested therapy is being used in combination with another approved acute or prophylactic HAE product when the policy prohibits combination use.

Background

Hereditary angioedema (HAE) is a rare genetic disorder caused by deficient or dysfunctional C1 esterase inhibitor (C1‑INH) or by pathogenic variants affecting bradykinin regulation, leading to recurrent episodic angioedema. C1‑INH replacement therapies (plasma‑derived or recombinant) and kallikrein‑inhibitor agents reduce bradykinin generation or activity and are used as on‑demand treatments for acute attacks or as prophylaxis to reduce attack frequency and severity.

Definitions and Diagnostic Criteria

inv-32: C1-INH deficiency (Type I/II)

C1-INH antigenic levelC1 inhibitor (C1-INH) antigenic level below the lower limit of normal

C1-INH functional levelC1-INH functional level below the lower limit of normal

Laboratory standardAbnormal antigenic or functional C1-INH documented per laboratory standard confirms Type I/II HAE

inv-33: HAE-unknown

Clinical definitionRecurring angioedema attacks refractory to high-dose antihistamines with unknown de-novo mutation(s) (no family history)

Alternative genetic contextIncludes patients with confirmed pathogenic variants in non-C1-INH genes (e.g., factor XII, plasminogen) per revised criteria

Revision History

2024-12-01policy_revisionLatest

Revised coverage criteria for initial therapy (Berinert, Ruconest, Kalbitor, and Cinryze): added coverage for patients with recurring angioedema attacks refractory to high‑dose antihistamines with unknown de‑novo mutation(s) (HAE‑unknown); expanded list of qualifying gene variants to include factor XII, angiopoietin‑1, plasminogen‑1, kininogen‑1, myoferlin, and HS3ST6; updated Clinical Evidence and References sections.

Policy Summary

PayerUnitedHealthcare

PolicyHereditary Angioedema (HAE), Treatment and Prophylaxis

Policy CodePolicy CS2024D0044S

Change TypeCoverage criteria revisedgenetic and clinical eligibility updated

Effective DateDec 1, 2024

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of diagnosis (C1‑INH deficiency or qualifying genetic variant or HAE‑unknown) and specialist prescriber attestation.

SourceLink

On This Page

Authorization duration: Reauthorization will be for no more than 12 months.

Physician attestation that the patient is unable to self-administer or there is no competent caregiver to administer the drug.

Clinical need: Prescriber attests patient has experienced attacks of a severity and/or frequency such that they would clinically benefit from prophylactic therapy with Cinryze.

Prior therapy or current use: Either history of failure, contraindication, or intolerance to Haegarda; OR patient is currently on Cinryze therapy.

Authorization duration: Authorization will be for no more than 12 months.

Efficacy timingMedian time to symptom relief generally within 37–90 minutes across studies

Denial risk when diagnosis not confirmed by laboratory or genetic testing per policy (see diagnostic requirements)

Denial risk when therapy is requested in combination with other approved HAE treatments for the same indication (acute or prophylaxis)

Documentation Required

Required Documentation — Diagnostic Laboratory and Genetic Testing

Providers must include clinical documentation to support the diagnosis and medical necessity. Required documentation includes laboratory confirmation of C1-INH deficiency or dysfunction (C1-INH antigenic level below the lower limit of normal or C1-INH functional level below the lower limit of normal) or, for HAE with normal C1-INH, appropriate genetic testing results and clinical history consistent with policy criteria.

C1-INH antigenic level and/or C1-INH functional level laboratory results when applicable
Genetic testing results for variant(s) (e.g., factor XII, plasminogen, angiopoietin-1, kininogen, myoferlin, HS3ST6) when diagnosis is HAE with normal C1-INH
Clinical history documenting recurring attacks refractory to high-dose antihistamines when applicable

Documentation Required

Home Therapy and Management Plan Documentation

For home therapy or self-administration, include documentation of a management plan and training showing patient or caregiver competency and suitability for self-administration. For agents where self-administration is not feasible or the patient/caregiver cannot perform administration, include physician attestation describing inability to self-administer or lack of a competent caregiver.

Home therapy management plan and training records
Attestation of patient/caregiver competency for self-administration, or physician attestation the patient is unable to self-administer / has no competent caregiver (required for Berinert, Ruconest, and Cinryze requests per policy)

Prior Authorization

Cinryze Prophylaxis — Required Documentation

For prophylactic use of Cinryze, document that the patient has experienced attacks of frequency and/or severity such that prophylaxis is clinically indicated and provide one of the following: history of failure, contraindication, or intolerance to Haegarda; or documentation that the patient is currently receiving Cinryze. Also document that Cinryze will not be used in combination with other prophylactic HAE products.

Clinical justification for prophylaxis (attack frequency/severity)
History of failure/contraindication/intolerance to Haegarda OR documentation patient is currently on Cinryze
Attestation that Cinryze will not be combined with other prophylactic agents (e.g., Haegarda, Takhzyro)

Documentation Required

Additional Documentation to Support Coverage

Include supporting clinical history and prior treatment trials where applicable (for example, use of on-demand therapies, trials of antihistamines, and prior prophylactic agents). When applicable, provide genetic testing and family history documentation for HAE-unknown or HAE with normal C1-INH. Failure to provide these items may result in denial.

Clinical history of HAE attacks and prior therapies/trials
Family history or documentation of de-novo mutation when HAE-unknown is claimed
Genetic test reports when indicated by policy

Coverage implicationHAE-unknown status is recognized for coverage when recurrent refractory angioedema is documented

inv-34: HAE-1/2 diagnostic tests

Recommended initial testsMeasure plasma C4 and C1-INH antigenic level

Functional testingMeasure C1-INH functional level when necessary to confirm diagnosis

Interpretation noteC4 alone should not be used to confirm or rule out HAE-1/2

inv-35: On-demand therapy

DefinitionOn-demand (acute) therapy: treatment administered to resolve symptoms of an acute HAE attack as soon as the attack is recognized

Agents includedIV C1-INH, subcutaneous ecallantide, or icatibant are recognized on-demand options

TimingAll attacks are eligible for early treatment; therapy should be available and given ideally before disabling symptoms develop

inv-36: Prophylaxis (short-term and long-term)

Short-term prophylaxisProphylaxis given around stressors or procedures likely to precipitate attacks (short-term) to prevent expected attacks

Long-term prophylaxisRegular prophylactic therapy to decrease the number and severity of recurrent HAE attacks when on-demand treatment is insufficient

Agent selection and individualizationPlasma‑derived C1‑INH, lanadelumab, and berotralstat are first-line long-term options; regimens should be individualized