CurrentUnitedHealthcarePolicy 2026 P 2232-9

Orladeyo (berotralstat) prior authorization/medical necessity

Defines UnitedHealthcare prior authorization and medical necessity criteria for coverage of Orladeyo (berotralstat) for prophylaxis of hereditary angioedema (HAE) in patients aged 2 years and older.

Policy Summary

PayerUnitedHealthcare

PolicyOrladeyo (berotralstat) prior authorization/medical necessity

Policy CodePolicy 2026 P 2232-9

Change TypeDiagnostic and prior-therapy updates

Effective DateApr 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization and document diagnosis, age-specific prior therapy failures, prescriber specialty, and dates/reasons for therapeutic failures.

SourceLink

POLICY UPDATE CHANGES

Andembry was added to the list of required preventive HAE agents for prior authorization.

Coverage criteria were updated to separate tried/failed therapies based on age limitations for Haegarda and Andembry per updated FDA indication.

Diagnostic criteria for HAE with normal C1 inhibitor levels were updated.

>=2 yearsminimum age for Orladeyo indication

12 monthsauthorization duration

3agents required (>=12 yrs)

Program Numberpolicy

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.

Coverage Criteria for Orladeyo (berotralstat)

Initial Authorization

Covered when ALL of the following are met:

Initial Authorization for Orladeyo

Diagnosis of HAE
- C1-INH deficiency/dysfunction: C1-INH antigenic level below the lower limit of normal OR C1-INH functional level below the lower limit of normal
  Type I or II HAE must be documented by laboratory standard
- HAE with normal C1-INH: Either a confirmed pathogenic variant in one of the genes (factor XII, angiopoietin-1, plasminogen-1, kininogen-1, myoferlin, HS3ST6) OR recurring angioedema refractory to high-dose antihistamines with confirmed family history OR recurring angioedema refractory to high-dose antihistamines with unknown de-novo mutation(s)
Indication and combination use: Prescribed for the prophylaxis of HAE attacks AND not used in combination with other approved prophylactic HAE products (Andembry, Cinryze, Dawnzera, Haegarda, Takhzyro)
Prescriber specialty: Prescribed by an immunologist or allergist
Age and prior therapy requirements
- Age 2–5 years: Patient is ≥ 2 years and < 6 years of age AND history of failure to Takhzyro (lanadelumab)
  Document date of trial and reason for therapeutic failure
- Age 6–11 years: Patient is ≥ 6 years and < 12 years of age AND history of failure to both Haegarda (C1 esterase inhibitor, human) AND Takhzyro (lanadelumab)
  Document date(s) of trial and reason(s) for therapeutic failure
- Age ≥12 years: Patient is ≥ 12 years of age AND history of failure to all of Andembry (garadacimab), Haegarda (C1 esterase inhibitor, human), AND Takhzyro (lanadelumab)
  Document date(s) of trial and reason(s) for therapeutic failure

Orladeyo (berotralstat) is not indicated for the treatment of acute HAE attacks. Coverage under this policy is focused on prophylactic use; Orladeyo is typically excluded from coverage for acute attack management and will only be considered when the specific prophylaxis criteria in this policy are met.

Orladeyo must not be used in combination with other products approved for HAE prophylaxis. Examples of prophylactic agents that cannot be used concomitantly with Orladeyo include Andembry, Cinryze, Dawnzera, Haegarda, and Takhzyro.

Use of Orladeyo for acute HAE attacks is similarly excluded under this policy; combination or acute-use scenarios are grounds for noncoverage unless the patient meets the documented prophylaxis criteria described elsewhere in this policy.

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for Orladeyo (berotralstat) for prophylaxis of hereditary angioedema (HAE). Authorization will be issued for 12 months. State mandates, federal requirements, and member-specific benefit plan coverage may affect coverage. Orladeyo is typically excluded from coverage; coverage reviews may occur if required by law or the benefit plan.

Prior authorization duration: 12 months
Do not combine Orladeyo with other approved prophylactic HAE products (Andembry, Cinryze, Dawnzera, Haegarda, Takhzyro)

Denial Risk

Triggers for Denial

Denial may be issued if confirmatory diagnostic documentation is not provided, if Orladeyo is prescribed for acute treatment of HAE attacks rather than prophylaxis, if Orladeyo is used in combination with other approved prophylactic HAE products, or if required documentation of prior therapy trials (including dates and reasons for therapeutic failure) is missing.

Definitions Related to Hereditary Angioedema

HAE with C1-INH deficiency (Type I or II) — diagnostic criteria

DefinitionHereditary angioedema (HAE) with C1-INH deficiency (Type I or II): documented by laboratory standard as either a C1-INH antigenic level below the lower limit of normal or a C1-INH functional level below the lower limit of normal.

Laboratory evidence (antigenic)C1-INH antigenic level below the lower limit of normal (per laboratory standard).

Laboratory evidence (functional)C1-INH functional level below the lower limit of normal (per laboratory standard).

Documentation requirementResult must be documented in the medical record using laboratory-standard reference ranges.

HAE with normal C1‑INH — diagnostic criteria

Definition

Background

Orladeyo (berotralstat) is a plasma kallikrein inhibitor approved for the prophylaxis of hereditary angioedema (HAE) attacks in adults and pediatric patients aged 2 years and older. It is intended to reduce the frequency of HAE attacks when used as ongoing preventive therapy and is not for acute attack treatment.

Revision History and Policy Changes

2026-04-01effective_dateLatest

Policy effective date updated to 2026-04-01 with separated age-based prior-therapy requirements for Haegarda and Andembry per updated FDA indications.

2026-01revision

Coverage criteria revised to separate tried/failed therapies based on age limitations for Haegarda and Andembry and background/references updated.

2025-11revision

Andembry was added to the list of required preventive HAE agents and examples of prophylactic HAE drugs updated to include Andembry and Dawnzera.

Policy Summary

PayerUnitedHealthcare

PolicyOrladeyo (berotralstat) prior authorization/medical necessity

Policy CodePolicy 2026 P 2232-9

Change TypeDiagnostic and prior-therapy updates

Effective DateApr 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization and document diagnosis, age-specific prior therapy failures, prescriber specialty, and dates/reasons for therapeutic failures.

SourceLink

On This Page

No confirmatory labs/genetic proof for HAE diagnosis
Use for acute/abortive treatment rather than prophylaxis
Missing documentation of prior therapy trials, dates, and reasons for failure
Concurrent use with other prophylactic HAE products

Documentation Required

Required Documentation to Support Prior Authorization

For prior authorization, submit documentation confirming the HAE diagnosis and that Orladeyo is prescribed for prophylaxis, including: laboratory confirmation of C1-INH deficiency or dysfunction OR genetic testing or clinical documentation for HAE with normal C1-INH; documentation of attack frequency/severity and prescriber attestation that patient would clinically benefit from prophylaxis; age-specific documented trials and documented therapeutic failures (dates and reasons) of required prior therapies; and the specialty of the prescriber (immunologist or allergist).

Diagnostic proof: C1-INH antigenic or functional level below lower limit of normal — OR genetic confirmation or clinical criteria for HAE with normal C1-INH
Provider attestation of attack frequency/severity and indication for prophylaxis
Required documentation of prior therapy trials with dates and reasons for failure (age-specific — see step therapy details)
Prescriber specialty: immunologist or allergist

Step Therapy

Required Prior Therapies by Age (Step Therapy)

Step therapy and required prior therapies vary by patient age. Document trials and reasons for therapeutic failure for the agents below before approving Orladeyo.

Ages 2 to <6 years: history of failure to Takhzyro (lanadelumab) (document date and reason)
Ages 6 to <12 years: history of failure to both Haegarda (C1 esterase inhibitor, human) and Takhzyro (lanadelumab) (document dates and reasons)
Ages ≥12 years: history of failure to all of the following — Andembry (garadacimab), Haegarda (C1 esterase inhibitor, human), and Takhzyro (lanadelumab) (document dates and reasons)

Hereditary angioedema (HAE) with normal C1-INH: confirmed by genetic testing showing pathogenic variant(s) in specified genes or by recurrent angioedema refractory to high‑dose antihistamines with supporting family history or de‑novo mutation evidence.

Genes specifiedConfirmed variant(s) in one or more of: factor XII, angiopoietin-1, plasminogen-1, kininogen-1, myoferlin, HS3ST6.

Clinical confirmation — family historyRecurring angioedema attacks refractory to high‑dose antihistamines with a confirmed family history of angioedema.

Clinical confirmation — de‑novoRecurring angioedema attacks refractory to high‑dose antihistamines with unknown background de‑novo mutation(s) (no family history).

2024-03revision

Annual review with update to diagnostic criteria for HAE with normal C1 inhibitor levels.

2021-08revision

Criteria updated to require failure of both Haegarda and Takhzyro for certain ages; reauthorization criteria removed and exclusion statement added.

2021-03creation

Prior authorization/medical necessity program for Orladeyo (berotralstat) established (new program).