CurrentmhnPolicy CP.PHAR.485

Clinical Policy: Berotralstat (Orladeyo)

Policy governs medical necessity criteria, prior authorization requirements, dosing limits, and continuation criteria for berotralstat (Orladeyo) for prevention of hereditary angioedema (HAE) attacks for commercial and Medicaid lines of business (excludes California Exchange Plans).

Policy Summary

Payermhn

PolicyClinical Policy: Berotralstat (Orladeyo)

Policy CodePolicy CP.PHAR.485

Change TypeClarified / Revised / Added

Effective DateDec 3, 2020

Next Review Date

Key ActionProvider must submit documentation (office notes, lab results, genetic testing, family history) supporting member meets all approval criteria.

POLICY UPDATE CHANGES

Clarified that these criteria do NOT apply to California Exchange Plans and directs requests to HIM.PA.169 for California Exchange Plans.

Updated FDA approved indication language to align with prescribing information.

Added redirection to Haegarda for prior therapy requirement in 06.02.21 revision.

Updated diagnosis criteria to include recurrent history of angioedema and either associated mutation or family history with failure of high-dose antihistamines for HAE-nl-C1INH.

FDA-approvedIndication: prophylaxis of HAE attacks

12+Age eligibility

150 mg/dayMaximum dose

6m / 12mApproval durations

Coverage Summary

Policy covers berotralstat (Orladeyo) for prevention (prophylaxis) of hereditary angioedema (HAE) attacks in patients aged ≥ 12 years when medical necessity criteria and prior authorization requirements are met; the policy governs dosing limits, prior authorization, and continuation criteria for commercial and Medicaid lines of business and excludes California Exchange Plans. Coverage stance: covered_with_criteria. Initial approval is for 6 months and continued approval for 12 months. Dosing limits: maximum 150 mg/day and no more than 1 capsule per day.

Quick Facts / Policy Thresholds

Minimum age≥ 12 years

Maximum daily dose150 mg/day; 1 capsule/day

High‑dose antihistamine trial (HAE‑nl‑C1INH)Cetirizine 40 mg/day (or equivalent) for ≥1 month or interval expected to be associated with ≥3 attacks

Approval durationsInitial: 6 months; Continued: 12 months

FDA‑approved indicationProphylaxis to prevent hereditary angioedema (HAE) attacks in patients ≥12 years; not for treatment of acute attacks

Initial Therapy Criteria — Hereditary Angioedema

Initial Approval Criteria - Hereditary Angioedema

Covered when ALL of the following are met:

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Initial Approval Criteria - Other diagnoses/indications

If request does not meet HAE criteria or recent label change applies:

Fallback - Other diagnoses/indications

Label change within last 6 months: If drug has had a label change within last 6 months not reflected in this policy, follow applicable formulary/no coverage or non-formulary policies (CP.CPA.190, CP.PMN.255, CP.PMN.16) as specified
Follow the referenced policies depending on formulary status and line of business

Continuation Therapy Criteria

Continued Therapy - Hereditary Angioedema

Covered when ALL of the following are met:

ALL of the following

Continuity of care: Member currently receiving medication via Centene benefit or previously met initial approval criteria; OR member is receiving medication and enrolled in state/product with continuity of care regulations (state addendums CC.PHARM.03A/03B apply)
Positive response: Member is responding positively to therapy as evidenced by a reduction in attacks from baseline
Provider must document reduction in attacks from baseline for continued approval
Combination therapy exclusion: Member is not using Orladeyo in combination with another FDA-approved product for long-term prophylaxis of HAE attacks (e.g., Cinryze, Haegarda, Takhzyro)

Unproven Uses / Exclusions

Diagnoses/Indications Not Authorized

Not covered when:

Not authorized indications: Non-FDA approved indications not addressed in this policy, unless sufficient documentation of efficacy and safety per off-label use policies (CP.CPA.09 commercial, CP.PMN.53 Medicaid) or evidence of coverage documents

Coverage for non-FDA approved uses requires supporting documentation per referenced off-label policies or evidence of coverage

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Applicable Codes

Product Dosage FormsNDC

110 mg capsule	Capsule strength available
150 mg capsule	Capsule strength available; standard dosing 150 mg PO QD

Provider Actions / Prior Authorization Requirements

Prior Authorization

Specialist prescription required

Prescription must be written by or in consultation with an allergist, hematologist, or immunologist.

Documentation Required

Documentation required

Submit clinical documentation to support the request, including office notes, laboratory results (C4, C1‑INH antigenic and/or functional levels), genetic testing when applicable, and relevant family history that demonstrates the diagnosis and meets the policy criteria.

Office chart notes documenting history of recurrent angioedema and frequency/severity of attacks
Laboratory results: C4 and C1‑INH antigenic or functional levels (or documentation of normal levels with genetic testing)
Genetic testing results, if available (for HAE-nl-C1INH)

Clinical Evidence

Evidence cited in the policy includes Phase 3 randomized, double-blind trials (APeX-2, APeX-S) demonstrating reduction in HAE attacks. The policy references the Orladeyo Prescribing Information: Orladeyo Prescribing Information, BioCryst; October 2024 (accessed April 25, 2025).

Trial Highlights / Evidence

Key RCTsPhase 3 randomized, double‑blind trials demonstrating efficacy in reducing HAE attacks (APeX‑2, APeX‑S)

PI sourceOrladeyo Prescribing Information, BioCryst; October 2024 (accessed April 25, 2025)

Background and Definitions

Berotralstat (Orladeyo) is an oral plasma kallikrein inhibitor indicated as prophylaxis to prevent HAE attacks in adults and pediatric patients 12 years and older; it should not be used for treatment of acute HAE attacks. Diagnosis requirements include laboratory confirmation for HAE-C1INH (low C4 and low C1‑INH antigenic or functional levels) or, for HAE‑nl‑C1INH, supporting evidence such as an associated mutation or family history of angioedema (with documented high‑dose antihistamine failure when applicable).

Term	Definition
{"text":"C1-INH","status":""},{"text":"C1 esterase inhibitor","status":""}
{"text":"C4","status":""},{"text":"Complement component 4","status":""}
{"text":"HAE-nl-C1INH","status":""},{"text":"Hereditary angioedema with normal C1 inhibitor (previously termed type III HAE; diagnosis may be supported by mutation or family history)","status":""}

Revision History

02.15.24clarified

Added clarification under description and initial approval criteria that these criteria do NOT apply to California Exchange Plans and directs requests to HIM.PA.169.

05.08.24clarified

Clarified wording that 'California Commercial Exchange Plans' refers to 'California Exchange Plans' (no significant changes to coverage).

06.02.21added

Per June SDC added redirection to Haegarda for prior therapy requirement (added redirection to Haegarda for prior therapy requirement).

Policy Summary

Payermhn

PolicyClinical Policy: Berotralstat (Orladeyo)

Policy CodePolicy CP.PHAR.485

Change TypeClarified / Revised / Added

Effective DateDec 3, 2020

Next Review Date

Key ActionProvider must submit documentation (office notes, lab results, genetic testing, family history) supporting member meets all approval criteria.

On This Page

Off-label referral: If requested use is not specifically listed under section III and above does not apply, refer to off-label use policy (CP.CPA.09 commercial, CP.PMN.53 Medicaid)

Refer to off-label use policies for commercial and Medicaid

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Dose increase limits

Max daily mg: 150 mg per day<= 150 mg/day
Max capsules: 1 capsule per day<= 1 capsule/day

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Continued Therapy - Other diagnoses/indications

If request does not meet HAE continuation criteria or recent label change applies:

Fallback - Other diagnoses/indications (continued)

Label change within last 6 months: If drug has had a label change within last 6 months not reflected in this policy, follow applicable formulary/no coverage or non-formulary policies (CP.CPA.190, CP.PMN.255, CP.PMN.16) as specified
Off-label referral: If requested use is not specifically listed under section III and above does not apply, refer to off-label use policy (CP.CPA.09 commercial, CP.PMN.53 Medicaid)

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Documentation of prior therapies and responses (e.g., high‑dose antihistamine trial, C1‑INH therapy)

Prior Authorization

Prior therapy requirement

Initial approval requires documentation of failure of Haegarda (C1 esterase inhibitor) unless the agent is contraindicated or the member experienced clinically significant adverse effects that preclude its use.

Document trial of Haegarda with dates and reason for discontinuation (lack of efficacy, intolerance, or contraindication)
If Haegarda not tried, provide rationale (e.g., contraindication or severe adverse reaction)

Billing Rule

Dose limits / Billing

Claims exceeding the policy dose limits may be denied. Ensure dosing and quantity billed do not exceed policy thresholds.

Maximum dose: 150 mg per day
Maximum quantity: 1 capsule per day

Documentation Required

Response documentation for continuation

For continued approval, submit documentation demonstrating a positive clinical response, defined as a reduction in HAE attacks from baseline while on therapy.

Documentation of baseline attack frequency and on‑therapy attack frequency
Clinical notes showing functional improvement or reduced healthcare utilization related to HAE

1Q 2022revised

1Q 2022 annual review updated diagnostic criteria to include recurrent history of angioedema and either associated mutation or family history with failure of high-dose antihistamines for HAE-nl-C1INH (updated diagnosis criteria and Appendix D ranges).

3Q 2025revisedLatest

3Q 2025 annual review updated FDA-approved indication language to align with prescribing information; no significant coverage changes.