CurrentUnitedHealthcarePolicy N/A

Hereditary Angioedema (HAE) specialty drug prior authorization

Defines prior authorization clinical and renewal criteria for multiple HAE therapies (Cinryze, Haegarda, Orladeyo, Takhzyro, Berinert, Firazyr, Kalbitor, Ruconest) for UnitedHealthcare members; applies to prescribers requesting coverage for prophylaxis or acute treatment.

Policy Summary

PayerUnitedHealthcare

PolicyHereditary Angioedema (HAE) specialty drug prior authorization

Policy CodePolicy N/A

Change TypeNo material change

Effective Date

Next Review Date

Key ActionComplete the agent-specific prior authorization checklist confirming diagnosis, indication, age eligibility, nonconcurrent use, and specialist involvement.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

8distinct HAE agents listed

6minimum ages vary

2required low C4

Coverage Criteria for HAE Therapies

Cinryze Initial Authorization

Cinryze — Covered when ALL of the following are met

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Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

Indication: Request is for prophylaxis of acute HAE attacks

Age: Beneficiary at least 6 years of age>=6 years

No concurrent therapy: Will not be used in combination with other prophylactic therapies targeting C1 inhibitor (e.g., Haegarda) or kallikrein (e.g., Takhzyro, Orladeyo)

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

Non-preferred product requirement: For non-preferred products, beneficiary has tried and failed or had insufficient response to at least two preferred products for the same indication OR there is a clinical reason preferred products cannot be tried2 preferred product failures

applies to non-preferred products

Haegarda Initial Authorization

Haegarda — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

Indication: Request is for prophylaxis of acute HAE attacks

Age: Beneficiary at least 6 years of age>=6 years

No concurrent therapy: Will not be used in combination with other prophylactic therapies targeting C1 inhibitor (e.g., Cinryze) or kallikrein (e.g., Takhzyro, Orladeyo)

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

Orladeyo Initial Authorization

Orladeyo — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

Indication: Request is for prophylaxis of acute HAE attacks

Age: Beneficiary at least 12 years of age>=12 years

No concurrent therapy: Will not be used in combination with other prophylactic therapies targeting C1 inhibitor (e.g., Cinryze, Haegarda) or kallikrein (e.g., Takhzyro)

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

Takhzyro Initial Authorization

Takhzyro — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

Indication: Request is for prophylaxis of acute HAE attacks

Age: Beneficiary at least 2 years of age>=2 years

No concurrent therapy: Will not be used in combination with other prophylactic therapies targeting C1 inhibitor (e.g., Cinryze, Haegarda) or kallikrein (e.g., Orladeyo)

applies to non-preferred products

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

Berinert Initial Authorization

Berinert — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

HAE with normal C1-INH with mutation: For HAE with normal C1-INH, patient has a known HAE-causing mutation (e.g., F12, angiopoietin-1, plasminogen, kininogen 1, myoferlin, HS3ST6)

mutation examples listed in document

Indication: Request is for treatment of acute abdominal, facial, or laryngeal HAE attacks

No concurrent acute therapies: Will not be used in combination with other approved treatments for acute HAE attacks (e.g., Firazyr, Ruconest, Kalbitor)

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

Firazyr Initial Authorization

Firazyr — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

HAE with normal C1-INH with mutation: For HAE with normal C1-INH, patient has a known HAE-causing mutation (e.g., F12, angiopoietin-1, plasminogen, kininogen 1, myoferlin, HS3ST6)

mutation examples listed in document

Indication: Request is for treatment of acute abdominal, facial, or laryngeal HAE attacks

Age: Beneficiary at least 18 years of age>=18 years

No concurrent acute therapies: Will not be used in combination with other approved treatments for acute HAE attacks (e.g., Berinert, Ruconest, Kalbitor)

applies to non-preferred products

Kalbitor Initial Authorization

Kalbitor — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

HAE with normal C1-INH with mutation or family history: For HAE with normal C1-INH, patient has a known HAE-causing mutation or family history of HAE

Indication: Request is for treatment of acute abdominal, facial, or laryngeal HAE attacks

No concurrent acute therapies: Will not be used in combination with other approved treatments for acute HAE attacks (e.g., Berinert, Firazyr, Ruconest)

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

Ruconest Initial Authorization

Ruconest — Covered when ALL of the following are met

Diagnosis and lab: Diagnosis of hereditary angioedema (HAE) I or II AND low C4 (C4 below the lower limit of normal as defined by the laboratory performing the test)

HAE with normal C1-INH with mutation or family history: For HAE with normal C1-INH, patient has a known HAE-causing mutation or family history of HAE

Indication: Request is for treatment of acute abdominal or facial HAE attacks

laryngeal attacks not listed for Ruconest in this checklist

No concurrent acute therapies: Will not be used in combination with other approved treatments for acute HAE attacks (e.g., Berinert, Firazyr, Kalbitor)

Specialist involvement: Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics

applies to non-preferred products

Renewal Criteria for All Agents

Renewal Criteria — Covered when ALL of the following are met

Continuation of initial criteria: Beneficiary continues to meet the initial criteria

Clinical benefit: Since starting the medication, beneficiary has experienced significant improvement in severity and duration of attacks and this improvement has been sustained

Tolerability: Beneficiary has not experienced unacceptable toxicity from the medication

The prior authorization checklists for each HAE agent include an explicit requirement that the requested product will not be used in combination with other specified HAE therapies. For prophylactic agents (e.g., Cinryze, Haegarda, Takhzyro, Orladeyo) the checklist asks whether the agent will not be used in combination with other prophylactic therapies targeting C1 inhibitor or kallikrein (see Cinryze, Haegarda, Orladyo, Takhzyro checklists). For acute treatments (e.g., Berinert, Firazyr, Kalbitor, Ruconest) the checklist asks whether the agent will not be used in combination with other approved treatments for acute HAE attacks (examples listed per agent).

Requests for coverage must therefore confirm non-concurrent use as a condition of approval; affirmative answers on the checklist are required and failure to attest to or meet this nonconcurrent-use requirement may result in denial. This non-concurrency requirement is applied on an agent-specific basis as listed in each product checklist and is part of the initial coverage criteria and renewal expectations for all agents.

In addition to the nonconcurrent-use requirement, the agent-specific checklists uniformly require documentation of diagnosis (HAE I/II with low C4 or, where applicable, HAE with normal C1‑INH plus a known mutation), the intended indication (prophylaxis versus treatment of acute attacks), age eligibility, and specialist prescribing or consultation. For non-preferred products some agents also require documentation of trial and failure of at least two preferred products or a clinical rationale why preferred products cannot be tried.

Prior Authorization and Provider Requirements

Prior Authorization

Agent-specific prior authorization checklist required

Prior authorization requires completion of the agent‑specific checklist for the requested product confirming diagnosis and required laboratory/testing. Complete all checklist items relevant to the product (e.g., diagnosis of HAE I or II or HAE with normal C1‑INH when applicable, and documentation of low C4 when required) and ensure prescriber specialty and age criteria are met.

Complete the product-specific checklist (Cinryze, Haegarda, Orladeyo, Takhzyro, Berinert, Firazyr, Kalbitor, Ruconest, etc.).
Document diagnostic criteria: HAE type and supporting labs (C4 below laboratory lower limit of normal when required).
Confirm prescriber is the appropriate specialist or consults with one (allergy, immunology, hematology, pulmonology, or medical genetics).

Step Therapy

Step therapy / preferred product trials

Step therapy or preferred‑product trial requirements apply to non‑preferred products. For non‑preferred requests, submit documentation of trials and failures (or clinical reasons why preferred products are not appropriate) — typically at least two preferred products for the same indication unless otherwise noted.

For non‑preferred product requests: evidence of trial and failure or inadequate response to at least two preferred products, or documentation of contraindication/intolerance to preferred options.
Examples appear in product checklists (see items referencing prior trials for Cinryze, Takhzyro, Firazyr, Kalbitor, Ruconest, etc.).

Documentation Required

Required request documentation

Include complete request documentation to allow timely review. Missing or incomplete submission fields may delay processing or result in denial.

Beneficiary identifiers: last name, first name, member ID, date of birth, gender.
Prescribing provider: name and NPI; requester contact name and phone (with extension).
Drug details: drug name, strength, quantity per 30 days, and requested length of therapy (select duration).
Clinical information: diagnosis, relevant laboratory results (e.g., C4 level with reference range), indication (prophylaxis vs treatment of acute attack), age of beneficiary, and whether product will be used in combination with other HAE therapies.

Denial Risk

Checklist nonconformity — denial risk

Failure to complete the required checklist items or to provide required documentation places the request at high risk of denial. Verify all checklist questions are answered and supporting labs/notes are uploaded before submission.

Checklist nonconformity examples: missing diagnosis, absent C4 result when required, age outside indicated range, lack of documentation of prior preferred product trials when required.
Incomplete administrative fields (missing member ID, prescriber NPI, contact info, or drug details) may also result in denial or processing delays.

Key Definitions and Diagnostic Criteria

HAE with normal C1-INH (formerly HAE III) — definition and mutation requirement

DefinitionHAE with normal C1-INH (formerly HAE III) is a subtype of hereditary angioedema where C1 inhibitor (C1-INH) levels are normal.

Policy requirement for acute agentsFor approval of certain acute HAE therapies (e.g., Berinert, Firazyr, Kalbitor, Ruconest), the policy requires the patient to have a known HAE-causing mutation when the diagnosis is HAE with normal C1-INH.

Examples of recognized mutationsDocument lists example mutations including coagulation factor XII gene (F12), angiopoietin-1, plasminogen, kininogen 1, myoferlin, and heparan sulfate 3-O sulfotransferase 6 (HS3ST6).

Alternate allowanceFor some agents (e.g., Kalbitor, Ruconest), a family history of HAE may be accepted in lieu of a known mutation per the checklist.

Specialist involvementRequests must be prescribed by or in consultation with a specialist in allergy, immunology, hematology, pulmonology, or medical genetics as indicated on agent checklists.

Low C4 — definition and diagnostic role

DefinitionLow C4 is defined as C4 below the lower limit of normal as defined by the laboratory performing the test.

Use in diagnosisA low C4 is required on the agent-specific prior authorization checklist to support a diagnosis of HAE types I or II for all listed agents (Cinryze, Haegarda, Orladeyo, Takhzyro, Berinert, Firazyr, Kalbitor, Ruconest).

Checklist phrasingEach agent-specific checklist asks: 'Does the beneficiary have a diagnosis of HAE I or II; AND Low C4 level (C4 below the lower limit of normal as defined by the laboratory performing the test)?'

ScopeLow C4 requirement appears across both prophylaxis and acute treatment agent checklists in the policy.

Laboratory referenceThe policy specifies the laboratory performing the test defines the lower limit of normal for C4; provider should document the lab reference range.

Background

Hereditary angioedema (HAE) management distinguishes between on‑demand (acute) therapies used to treat individual abdominal, facial, or laryngeal attacks and prophylactic therapies intended to prevent or reduce the frequency and severity of attacks. The policy’s checklists reflect this distinction by separating product-specific indications: several agents are authorized for chronic prophylaxis while others are authorized for treatment of acute attacks.

The documentation required for either strategy centers on confirming the HAE subtype and relevant laboratory evidence. For HAE type I or II the checklists require a diagnosis plus a documented low C4 (C4 below the laboratory’s lower limit of normal). For some agents and indications (particularly for HAE with normal C1‑INH, formerly HAE III) the checklist requires a known HAE‑causing mutation or appropriate family history. Age thresholds and specialist involvement vary by agent and are specified in each agent’s criteria.

Policy Summary

PayerUnitedHealthcare

PolicyHereditary Angioedema (HAE) specialty drug prior authorization

Policy CodePolicy N/A

Change TypeNo material change

Effective Date

Next Review Date

Key ActionComplete the agent-specific prior authorization checklist confirming diagnosis, indication, age eligibility, nonconcurrent use, and specialist involvement.

SourceLink

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