CurrentPeach State Health PlanPolicy CP.PHAR.202

C1 Esterase Inhibitors (Berinert, Cinryze, Haegarda, Ruconest)

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Prior authorization and medical necessity criteria for C1 esterase inhibitor products for the treatment and prophylaxis of hereditary angioedema (HAE) for Peach State Health Plan members (Commercial and Medicaid).

Policy Summary

PayerPeach State Health Plan

PolicyC1 Esterase Inhibitors (Berinert, Cinryze, Haegarda, Ruconest)

Policy CodePolicy CP.PHAR.202

Change TypeNo material changes

Effective DateMar 1, 2016

Next Review DateAug 25, 2025

Key ActionPrior authorization is required for Berinert, Cinryze, Haegarda, and Ruconest and requests must include documentation showing all approval criteria are met.

SourceLink

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CurrentPeach State Health PlanPolicy CP.PHAR.202

C1 Esterase Inhibitors (Berinert, Cinryze, Haegarda, Ruconest)

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Policy Summary

PayerPeach State Health Plan

PolicyC1 Esterase Inhibitors (Berinert, Cinryze, Haegarda, Ruconest)

Policy CodePolicy CP.PHAR.202

Change TypeNo material changes

Effective DateMar 1, 2016

Next Review DateAug 25, 2025

Key ActionPrior authorization is required for Berinert, Cinryze, Haegarda, and Ruconest and requests must include documentation showing all approval criteria are met.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

J0596-J0599HCPCS codes referenced

4Products covered

YesPA required

YesDose limits included

VariesAge limits

Coverage Criteria

Initial Therapy (Hereditary Angioedema)

Covered when ALL of the following are met for hereditary angioedema (HAE):

HAE diagnosis confirmation: Diagnosis of HAE confirmed by a history of recurrent angioedema AND one of the following: (a) low C4 level and low C1‑INH antigenic or functional level (see Appendix D) OR (b) normal C4 and normal C1‑INH levels plus (i) presence of a mutation associated with the disease OR (ii) family history of angioedema and documented failure of high‑dose antihistamine therapy (e.g., cetirizine 40 mg/day or equivalent) for at least 1 month or an interval expected to be associated with ≥3 attacks, whichever is longer.see Appendix D for lab reference ranges

From Initial Approval Criteria section

Prescriber specialty: Prescribed by or in consultation with a hematologist, allergist, or immunologist.

Criterion 2

Age/product eligibility: Member meets one of: (a) Age ≥5 years for Berinert; (b) Age ≥6 years for Cinryze or Haegarda; (c) Age ≥13 years for Ruconest.

Criterion 3

Indication-specific limits: Member meets one of: (a) Acute treatment: request does not exceed 4 doses per month AND request is for Berinert OR request is for Ruconest when member does not experience laryngeal attacks; (b) Long‑term prophylaxis: request is for Cinryze or Haegarda AND member experiences >1 severe event/month OR is disabled >5 days/month OR has history of prior airway compromise; (c) Short‑term prophylaxis: member requires major dental work or surgical procedure AND request does not exceed 2 doses per procedure.dose/frequency limits defined

Criterion 4

Step and co‑therapy restrictions: If request is for treatment of acute HAE attacks and member is age ≥18 years, failure of icatibant (Firazyr) is required unless contraindicated or clinically significant adverse effects occur; member must not be using the requested product in combination with another FDA‑approved product for the same indication.

Criteria 5 and 7

Dose maximums: Dose must not exceed product‑specific maximums: Berinert 20 IU/kg per single dose (up to 2 doses in 24 hours); Cinryze 2,000 units every 3–4 days; Haegarda 60 IU/kg per dose twice weekly; Ruconest 4,200 IU per single dose (up to 2 doses in 24 hours).product‑specific

Criterion 8; see Dosage and Administration

Continued Therapy

Continued therapy requirements differ by indication:

Short-term prophylaxis re-authorization: Re-authorization for short‑term prophylaxis is not permitted; members must meet the initial approval criteria (approval duration: not applicable).

Section II.A

Other indications continued therapy: Member meets one of: (a) currently receiving medication via Centene benefit or previously met initial approval criteria; OR (b) member is receiving medication and is enrolled in a state/product with continuity‑of‑care regulations. Additionally: member is responding positively to therapy (e.g., reduction in attacks from baseline), member is not using the requested product in combination with another FDA‑approved product for the same indication, for acute attacks request does not exceed 4 doses/month, and any dose increase does not exceed the product‑specific maxima.

Section II.B

Other Indications / Label Changes

For indications not explicitly covered:

Recent label change: If the drug underwent a label change within the last 6 months that is not yet reflected in this policy (e.g., new indication, age expansion, dosing), follow the referenced formulary/no‑coverage or non‑formulary policies for the relevant line of business.6 months

Section I.B and IV.C

Off‑label requests: If the requested use (diagnosis, age, dosing) is not listed and criterion 1 above does not apply, refer to the off‑label use policy for the relevant line of business (CP.CPA.09 for commercial; CP.PMN.53 for Medicaid).

Section I.B

Indication-specific dosing coverage

Coverage and dosing per indication as described in dosing table and diagnosis sections

Product indications: Products are indicated for either treatment of acute HAE attacks or prophylaxis depending on product: Berinert and Ruconest for acute treatment; Haegarda and Cinryze for prophylaxis. Short‑term prophylaxis before invasive procedures may use a single dose of 20 IU/kg plasma‑derived C1 inhibitor given 1–12 hours before the procedure; on‑demand treatment should be available if delayed swelling occurs.

See Dosage and Administration and Appendix D

Requests for uses that are not included in the FDA-approved labeling and not specifically addressed by this policy are not authorized unless the provider supplies sufficient documentation of efficacy and safety in accordance with the applicable off‑label use policy (see CP.CPA.09 for commercial members and CP.PMN.53 for Medicaid).

Use of Ruconest is contraindicated in patients with a known or suspected allergy to rabbits or rabbit‑derived products. Additionally, Ruconest, Berinert, Cinryze, and Haegarda should not be used in patients with a history of immediate or life‑threatening hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations. Note that effectiveness of Ruconest was not established in patients who experience laryngeal attacks; exercise clinical judgment and provide supporting documentation when considering treatment in these scenarios.

The safety and efficacy of Berinert for prophylactic therapy have not been established; therefore requests for prophylactic use of Berinert are considered not authorized unless compelling evidence consistent with the off‑label use policies is provided. More broadly, non‑FDA labeled uses for any C1 esterase inhibitor require sufficient supporting clinical documentation per the plan's off‑label coverage requirements.

HCPCS and other codes listed in this policy are provided for informational purposes only. Inclusion or exclusion of any code does not guarantee coverage; coverage decisions are determined by whether the member meets the medical necessity criteria and the terms of the member's benefit. Providers should verify coding guidance prior to claim submission.

Coding and Codes Referenced

HCPCS Codes referencedHCPCS

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

Cinryze maximum dose

Maximum per dosing interval2,000 units (4 vials)

Provider Actions and Requirements

Prior Authorization

Prior authorization required for all listed C1 esterase inhibitors

Prior authorization is required for Berinert, Cinryze, Haegarda, and Ruconest; requests must include documentation demonstrating that all approval criteria are met (diagnosis, prescriber specialty, age, indication-specific limits, step therapy where applicable, and dosing within product-specific maximums).

Include evidence of HAE diagnosis per policy (see Appendix D lab criteria or mutation/family history pathways).
Ensure prescriber is a hematologist, allergist, or immunologist or consult documentation is provided.
Confirm age eligibility for the requested product (Berinert ≥5, Cinryze/Haegarda ≥6, Ruconest ≥13).
Document indication-specific dose/frequency does not exceed policy limits.

Initial Therapy Criteria

Initial Therapy

Initial approval — top‑level criteria (diagnosis, prescriber, age, indication frequency limits, step therapy):

Diagnosis and prescriber: Diagnosis of HAE as specified in criteria (history of recurrent angioedema with required laboratory confirmation or mutation/family history plus antihistamine failure) AND prescribed by or in consultation with a hematologist, allergist, or immunologist.see Appendix D

Top‑level initial approval requirements

Age eligibility: Member meets one of: Age ≥5 years for Berinert; Age ≥6 years for Cinryze or Haegarda; Age ≥13 years for Ruconest.

Age/product criteria

Indication frequency and product limits: Member meets one of: (a) Acute treatment — request ≤4 doses/month and is for Berinert OR for Ruconest if no laryngeal attacks; (b) Long‑term prophylaxis — request is for Cinryze or Haegarda and member has >1 severe event/month OR is disabled >5 days/month OR has prior airway compromise; (c) Short‑term prophylaxis — requirement for major dental work or surgery and request ≤2 doses per procedure.

Continuation / Continued Therapy Criteria

Continued Therapy

Continued therapy — required documentation and criteria for continued approval (except short‑term prophylaxis):

Eligibility for continued therapy: Member is currently receiving the medication via the Centene benefit or previously met initial approval criteria OR is in continuity‑of‑care eligible state/product as applicable.

Continued Therapy II.B.1

Clinical response: Member is responding positively to therapy (e.g., demonstrable reduction in HAE attacks from baseline) or request is for an appropriate dose increase with documented clinical rationale.

Continued Therapy II.B.2

No concomitant same‑indication therapy: Member is not using the requested product in combination with another FDA‑approved product for the same indication (e.g., combination of Berinert, Firazyr, Kalbitor, Ruconest for acute attacks or combination of Cinryze, Haegarda, Orladeyo, Takhzyro for prophylaxis).

Continued Therapy II.B.3

Step Therapy Requirements

Step	Requirement	Applies to / Notes
1	Trial and failure of icatibant (Firazyr) is required prior to approval unless contraindicated or clinically significant adverse effects are experienced.	Adults age ≥18 years requesting treatment for acute hereditary angioedema (HAE) attacks; prior authorization for icatibant may be required.

Step	Requirement	Applies to / Notes
2	Failure of Haegarda (or intolerance) is required before other long-term prophylaxis products may be approved, unless contraindicated or significant adverse effects are experienced.	Requests for long-term prophylaxis of HAE attacks (e.g., alternatives to Haegarda such as Cinryze or other prophylactic agents).

Step	Requirement	Applies to / Notes
Refer to full policy	See the full policy for explicit step therapy sequencing, enforced redirections, and any age restrictions (example: Firazyr redirection applies to members age ≥18 years).	Policy includes prior internal redirections to Firazyr for acute attacks and to Haegarda for prophylaxis; consult policy Appendix and review notes for details.

Quantity and Dosing Limits by Product

Berinert dosing limits

Per-dose limit20 IU/kg of body weight per single dose

24-hour limitUp to 2 doses administered in a 24-hour period

IndicationTreatment of acute HAE attacks (IV)

Cinryze dosing limits

Recommended dosing interval2,000 units every 3 to 4 days

Maximum per dosing interval2,000 units (4 vials) per dosing interval

Age-specific dosingAge 6-11 years: 500 units every 3–4 days; Age ≥12 years: up to 2,000 units every 3–4 days (not exceeding 80 units/kg)

Site of Care and Administration Settings

Note

Site of care: IV and SC formulations; home/clinic/infusion/hospital

C1 esterase inhibitor products are available as IV and SC formulations; administration may occur in home, office, infusion center, or hospital outpatient settings. Short‑term prophylaxis dosing (e.g., single dose of plasma‑derived C1 inhibitor) may be given 1–12 hours prior to an invasive procedure.

Settings: home, office, infusion center, hospital outpatient
Short‑term prophylaxis timing: single dose 1–12 hours before procedure

Background

Hereditary angioedema (HAE) is characterized by recurrent episodes of angioedema. Most cases are due to deficiency or dysfunction of the C1 esterase inhibitor (C1‑INH), classically labeled Type I or II HAE, and are typically associated with low C4 levels and low antigenic or functional C1‑INH. A distinct group, HAE with normal C1‑INH (HAE‑nl‑C1INH), presents with normal C4 and C1‑INH levels and may be associated with specific genetic mutations; diagnosis of HAE in all cases relies on compatible clinical history (recurrent angioedema) plus appropriate laboratory testing or genetic/family history as described in the diagnostic criteria. C1 esterase inhibitor products are used either to treat acute HAE attacks (for example, Berinert and Ruconest) or to provide prophylaxis against HAE attacks (for example, Haegarda and Cinryze) depending on the product and labeled indication.

Definitions

C1 esterase inhibitor (C1-INH) definition

AbbreviationC1-INH = C1 esterase inhibitor

Related lab testsC4 complement component often low in HAE with C1-INH deficiency

RoleUsed therapeutically as replacement or recombinant C1 esterase inhibitor products for HAE treatment/prophylaxis

HAE-nl-C1INH (short definition)

Short labelHAE-nl-C1INH: hereditary angioedema with normal C1-INH

Also known asPreviously referred to as type III HAE (term obsolete)

Laboratory finding

Policy Summary

PayerPeach State Health Plan

PolicyC1 Esterase Inhibitors (Berinert, Cinryze, Haegarda, Ruconest)

Policy CodePolicy CP.PHAR.202

Change TypeNo material changes

Effective DateMar 1, 2016

Next Review DateAug 25, 2025

Key ActionPrior authorization is required for Berinert, Cinryze, Haegarda, and Ruconest and requests must include documentation showing all approval criteria are met.

SourceLink

On This Page

PA required for C1 esterase inhibitor HCPCS (J0596–J0599)

Prior authorization is required when billing C1 esterase inhibitor products with HCPCS codes J0596–J0599; the billed dosing and indication must match the policy criteria (acute treatment vs prophylaxis) and supporting documentation must be provided.

J0596 (Ruconest), J0597 (Berinert), J0598 (Cinryze), J0599 (Haegarda) must have PA with documentation of indication and dose consistent with policy dosing limits.
Coding inclusion is informational only; coverage depends on meeting medical necessity and benefit terms.

Step Therapy

Step requirement: trial of icatibant (Firazyr) for acute attacks in adults

For treatment of acute HAE attacks in adults (age ≥18 years), a trial and failure of icatibant (Firazyr) is required prior to approval of C1 esterase inhibitor products unless icatibant is contraindicated or causes clinically significant adverse effects.

Icatibant dosing per Appendix B: 30 mg SC; additional injections may be given at ≥6-hour intervals, not to exceed 3 injections/24 hours.
Note that prior authorization may itself be required for icatibant.

Note

Historical redirects to Firazyr for acute treatment and Haegarda for prophylaxis

The policy record notes prior internal redirection to icatibant (Firazyr) for acute HAE treatment and to Haegarda for prophylaxis per earlier clinical guidance; reviewers should reference historical clinical notes and prior guidance when applying step/redirection rules.

June 2021 and subsequent reviews added redirection to Firazyr for acute attacks and Haegarda for prophylaxis.
Template and review notes may affect enforcement of redirections; refer to full policy review history for specifics.

Documentation Required

Required supporting documentation (chart notes, labs, consults)

Providers must submit supporting clinical documentation with PA requests such as office chart notes, laboratory results, or other clinical information that demonstrate the member meets all approval criteria.

Acceptable documents include office/clinic notes describing history of recurrent angioedema and attack frequency, consultation notes, and treatment records.
Include documentation of prior step therapy trials or contraindications when applicable.

Documentation Required

Laboratory confirmation: C4 and C1‑INH antigenic/functional levels

Laboratory confirmation may be used to verify HAE Type I or II: submit C4 level and C1‑INH antigenic and/or functional assay results with laboratory reference ranges from an accredited lab.

C4 reference ranges and C1‑INH antigenic/functional reference values are listed in Appendix D (e.g., C1‑INH functional: normal >67% per listed labs).
For HAE with normal C1‑INH, documentation of a disease-associated mutation or family history plus antihistamine failure may be required.

Denial Risk

Denial risk if documentation or criteria are not met

Lack of required documentation that the member meets all approval criteria (diagnosis confirmation, appropriate prescriber specialty, age eligibility, indication limits, step therapy, or dosing within maxima) may result in denial of the request.

Denials may occur if charts, labs, or consult notes are not submitted or do not support the requested indication or dosing.
Ensure documentation of prior icatibant trial or documented contraindication when step therapy applies.

Denial Risk

Contraindicated hypersensitivity and rabbit allergy — deny if present

Requests will be contraindicated and may be denied for members with a history of immediate or life‑threatening hypersensitivity reactions (including anaphylaxis) to C1 esterase inhibitor preparations; Ruconest is specifically contraindicated in members with known or suspected allergy to rabbits or rabbit‑derived products.

Document any history of hypersensitivity or rabbit allergy; absence of such documentation may preclude approval.
Do not approve Ruconest for patients with known/suspected rabbit or rabbit‑derived product allergy.

dose/frequency limits defined

Indication‑specific limits

Step therapy for acute and prophylaxis: If request is for acute attacks and member ≥18 years, failure of icatibant (Firazyr) is required unless contraindicated; if request is for long‑term prophylaxis, failure of Haegarda is required unless contraindicated. Member must not be using the requested product in combination with another FDA‑approved product for the same indication.

Step requirements

Dose limits: Requested dose must not exceed product maximums (Berinert 20 IU/kg single dose up to 2 doses/24 hr; Cinryze 2,000 units every 3–4 days; Haegarda 60 IU/kg twice weekly; Ruconest 4,200 IU single dose up to 2 doses/24 hr).product‑specific

Dose maximums per product

Initial therapy dosing

Initial therapy dosing — product‑specific labeled dosing and short‑term prophylaxis timing:

Berinert dosing (acute): Berinert for treatment of acute HAE attacks: 20 IU/kg body weight IV per dose (weight‑based); dosing per PI and vial sizes apply; may administer up to 2 doses within 24 hours as needed.20 IU/kg; up to 2 doses/24 hr

See Dosage and Administration table

Ruconest dosing (acute): Ruconest for treatment of acute HAE attacks: Weight <84 kg: 50 IU/kg IV; Weight ≥84 kg: 4,200 units IV. A second dose may be administered per product labeling; Ruconest not for members who experience laryngeal attacks per indication limits.50 IU/kg (<84 kg) or 4,200 IU (≥84 kg); up to 2 doses/24 hr

See Dosage and Administration table

Haegarda dosing (prophylaxis): Haegarda for prophylaxis against HAE attacks: 60 IU/kg body weight SC twice weekly (every 3 or 4 days); dose based on weight per labeling.60 IU/kg twice weekly

See Dosage and Administration table

Cinryze dosing (prophylaxis): Cinryze for prophylaxis against HAE attacks: Age 6–11 years: 500 units IV every 3–4 days; Age ≥12 years: 1,000 units IV every 3–4 days (maximum per interval: age‑based up to 2,000 units as indicated and not to exceed 80 units/kg).Age‑based dosing; max 2,000 units per interval

See Dosage and Administration table

Short‑term prophylaxis timing: For short‑term prophylaxis prior to invasive procedures, a single dose of 20 IU/kg plasma‑derived C1 inhibitor may be given 1–12 hours before the stressor; on‑demand treatment should be available for delayed swelling.1–12 hours pre‑procedure; single dose

Appendix D recommendation

Acute use frequency limit: For treatment of acute attacks, continued use must not exceed 4 doses per month.≤4 doses/month

Continued Therapy II.B.4

Dose increase limits: If a dose increase is requested, the new dose must not exceed product‑specific maximums (Berinert 20 IU/kg single dose up to 2 doses/24 hr; Cinryze 2,000 units every 3–4 days; Haegarda 60 IU/kg twice weekly; Ruconest 4,200 IU single dose up to 2 doses/24 hr).product‑specific

Continued Therapy II.B.5

Required documentation: Provider must submit documentation (office/chart notes, lab results, or other clinical information) supporting that the member meets continued therapy criteria, including laboratory confirmation when applicable.

Documentation expectation

Continued therapy notes

Notes affecting continued therapy language and historical template updates:

Template and history notes: Template changes and prior clinical guidance have redirected some acute HAE treatment to icatibant (Firazyr) and prophylaxis to Haegarda in prior reviews; these historical notes may affect how continued therapy language appears in templates but do not change the substantive clinical criteria herein. Refer to full policy revision history for details.

Reviews and Revisions section

Step therapy implications: Per prior P&T and clinical guidance, trials of icatibant (age ≥18) for acute attacks and failure/intolerance of Haegarda for prophylaxis are referenced as step requirements; check the step therapy section for enforced steps and age restrictions.

See step therapy and prior guidance

Haegarda dosing limits

Per-dose regimen60 IU/kg per dose, administered subcutaneously twice weekly (every 3 or 4 days)

IndicationProphylaxis against HAE attacks (SC)

Maximum per doseBased on weight: 60 IU/kg/dose

Ruconest dosing limits

Per-dose limit4,200 IU per single dose for adults ≥84 kg; (alternatively 50 IU/kg IV for weight <84 kg)

24-hour limitMay administer a second dose; up to 2 doses within a 24-hour period

IndicationTreatment of acute HAE attacks (recombinant, IV)

Cinryze — maximum per dosing interval (updated)

Restated maximum2,000 units maximum per dosing interval (per 3Q 2023 PI update)

Vial size referenceCinryze available as 500-unit vials

Age noteDose varies by age: younger children have lower per-dose units (see product labeling)

Berinert vial and dosing note

Vial sizeBerinert vial with powder for reconstitution: 500 IU

Dosing referenceDose calculated by weight: 20 IU/kg per single IV dose (per PI)

IndicationTreatment of acute HAE attacks (IV)

Normal C4 and normal C1-INH levels

HAE-nl-C1INH — expanded definition

Expanded definitionHereditary angioedema with normal C1-INH levels; presents with normal C4 and C1-INH antigenic and functional levels

Genetic associationMay be associated with mutations in genes such as F12, ANGPT1, PLG, KNG1, MYOF, HS3ST6

Diagnostic noteVery rare; no definitive laboratory test—diagnosis may rely on genetic testing and clinical history