CurrentCignaPolicy IP0315

Intravenous C1 Esterase Inhibitors (Berinert, Cinryze, Ruconest) for Hereditary Angioedema (HAE)

Cigna coverage policy governing medical necessity, continuation, dosing, non-covered uses, and coding for intravenous C1 esterase inhibitor therapies (Berinert, Cinryze, Ruconest) for treatment and prophylaxis of hereditary angioedema across applicable Cigna-administered health benefit plans.

Policy Summary

PayerCigna

PolicyIntravenous C1 Esterase Inhibitors (Berinert, Cinryze, Ruconest) for Hereditary Angioedema (HAE)

Policy CodePolicy IP0315

Change TypeAnnual revision — no criteria changes

Effective DateJan 15, 2025

Next Review Date

Key ActionProviders must obtain authorization demonstrating the patient meets diagnostic and treatment criteria, including genetic testing or laboratory evidence of low C4 plus low functional or antigenic C1‑INH.

SourceLink

POLICY UPDATE CHANGES

Annual revision performed with no criteria changes.

3C1-INH products addressed (Berinert, Cinryze, Ruconest)

12Initial and reauthorization approval duration

20 IU/kgMax Berinert/Cinryze acute dose

4,200Max Ruconest dose per administration

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Medically Necessary and Excluded Uses

Medically Necessary — Berinert or Cinryze

IV C1-INH (Berinert or Cinryze) considered medically necessary when the individual meets ONE of the following (prophylaxis or acute treatment) and associated subcriteria:

ANY of the following

HAE - Prophylaxis
- ALL of the following
  - Confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1 gene
  - ALL of the following
    Low functional C1-INH protein (< 50% of normal) at baseline as documented by laboratory reference values
    OR low C1-INH antigenic levels (< 50% of normal) at baseline as documented by laboratory reference values
    Either low functional OR low antigenic satisfies this branch
- Berinert or Cinryze will not be concomitantly administered with other FDA‑approved prophylactic treatments for HAE (e.g., Haegarda, Takhzyro, Orladeyo)
  Concomitant prophylactic therapy with other listed agents is exclusionary
- Medication is prescribed by, or in consultation with, an allergist/immunologist
- ANY of the following
  - Age ≥ 12 years: up to a maximum dose of 2,500 units (not exceeding 100 units/kg), IV, no more frequently than twice weekly with doses separated by at least 3 days
  - Age < 12 years: up to a maximum dose of 1,000 units, IV, no more frequently than twice weekly with doses separated by at least 3 days
HAE - Treatment of Acute Attacks
- ANY of the following
  - Confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1 gene
  - ANY of the following
    Low functional C1-INH protein (< 50% of normal) at baseline as documented by laboratory reference values
    Low C1-INH antigenic levels (< 50% of normal) at baseline as documented by laboratory reference values
- Berinert or Cinryze will not be concomitantly administered with other FDA‑approved prophylactic treatments for HAE (examples listed include Firazyr/icatibant, Kalbitor, Ruconest, or Sajazir)
  Concomitant use with listed agents is exclusionary

Medically Necessary — Ruconest

Ruconest is considered medically necessary for treatment of acute HAE attacks when ALL of the following are met:

ALL of the following

ANY of the following
- Confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1 gene
- ANY of the following
  - Low functional C1-INH protein (< 50% of normal) at baseline as documented by laboratory reference values
  - Low C1-INH antigenic levels (< 50% of normal) at baseline as documented by laboratory reference values
Ruconest will not be concomitantly administered with other FDA‑approved prophylactic treatments for HAE (examples include Berinert, Cinryze, Firazyr/icatibant, Kalbitor, Sajazir)

Continuation / Reauthorization Criteria — Berinert or Cinryze

Continuation is medically necessary when ONE of the following for prophylaxis or acute treatment is met:

ANY of the following

Prophylaxis continuation
- Initial medical necessity criteria were met prior to start of therapy
- Documentation of beneficial response since initiating prophylactic therapy (e.g., decreased attack frequency, severity, or duration)
- Medication continues to be prescribed by, or in consultation with, an allergist/immunologist
Acute treatment continuation
- Initial medical necessity criteria were met prior to start of therapy

Continuation / Reauthorization Criteria — Ruconest

Continuation of Ruconest for acute attacks is medically necessary when ALL of the following are met:

ALL of the following

Initial medical necessity criteria were met prior to start of Ruconest therapy
Documentation of beneficial response since initiating Ruconest therapy (examples: decreased duration of attacks, quick onset of symptom relief, complete resolution, decreased frequency/severity)
Medication continues to be prescribed by, or in consultation with, an allergist/immunologist

Conditions Not Covered (Experimental/Investigational/Unproven)

Uses not covered include (not all inclusive):

ANY of the following

Ruconest for long‑term prophylaxis of HAE (Ruconest is not FDA‑approved for prophylaxis and current evidence is insufficient)
Episodes of angioedema with normal C1‑INH levels/function that are not related to a documented pathogenic variant mutation in F12, ANGPT1, PLG, or KNG1

Relevant Billing Codes

Drug HCPCS codes (considered medically necessary when criteria met)HCPCSCovered

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

Authorization, Documentation, and Denial Risks

Prior Authorization

Authorization required under medical necessity criteria

Providers must obtain prior authorization consistent with the policy showing the patient meets diagnostic and treatment criteria before C1‑INH therapy is approved. Acceptable diagnostic evidence includes genetic testing showing a confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1 OR laboratory evidence of one C4 level below the laboratory lower limit of normal plus either low functional C1‑INH (<50% of normal) or low C1‑INH antigenic level (<50% of normal).

J0596
J0597
J0598

Documentation Required

Diagnostic documentation required

Document diagnostic confirmation of HAE by either: a confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1; OR laboratory reports showing one C4 level below the laboratory lower limit of normal plus either a C1‑INH functional level <50% of normal or a C1‑INH antigenic level <50% of normal, as defined by the performing laboratory.

Documentation Required

Benefit/response documentation for continuation

For reauthorization, include documentation that initial medical necessity criteria were previously met and that the member has had a beneficial response to therapy (examples: reduced attack frequency, severity, or duration for prophylaxis; decreased duration of attacks, rapid symptom relief, or complete resolution for acute treatment). Also document that the medication continues to be prescribed by, or in consultation with, an allergist/immunologist.

Denial Risk

Concomitant therapy exclusion

Requests will be denied if the requested C1‑INH product is intended to be administered concomitantly with other FDA‑approved prophylactic HAE treatments; concomitant prophylactic therapy with listed agents is exclusionary per the policy.

J0597
J0598

Denial Risk

Non‑covered indications

Ruconest when requested for long‑term prophylaxis, and use of C1‑INH for episodes of angioedema with normal C1‑INH levels/function without a documented pathogenic variant in F12, ANGPT1, PLG, or KNG1, are considered experimental/investigational and are non‑covered per the policy.

J0596

Clinical Context and Diagnostic Evaluation

Berinert and Cinryze are human plasma‑derived C1‑esterase inhibitor (C1‑INH) replacement therapies and Ruconest is a recombinant C1‑INH. These agents are used in hereditary angioedema (HAE): Berinert and Ruconest are labeled for treatment of acute HAE attacks, while Cinryze is labeled for routine long‑term prophylaxis; clinical practice and literature also report use of plasma‑derived C1‑INH products across both acute and prophylactic settings. Plasma‑derived C1‑INH and other agents (for example, subcutaneous C1‑INH, lanadelumab, or berotralstat) are considered first‑line options for long‑term prophylaxis depending on individual patient needs and preferences, whereas plasma‑derived C1‑INH and Ruconest are first‑line options for on‑demand treatment of acute attacks. (See product prescribing information for specific labeled indications.)

Diagnostic evaluation of suspected HAE should include measurement of serum C4, C1‑INH antigenic (protein) concentration, and C1‑INH functional activity. A pattern of low C4 plus low C1‑INH antigenic or functional level is consistent with a diagnosis of HAE types I or II. Policy thresholds use C1‑INH antigenic or functional level < 50% of normal (baseline, as documented by laboratory reference values) and a C4 level below the laboratory lower limit of normal to establish laboratory evidence supporting the diagnosis; alternatively, documentation of a confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1 also confirms the diagnosis for coverage purposes.

Clinical Thresholds and Dose Limits

Policy Thresholds

C1‑INH functional level< 50% of normal (baseline), as documented by laboratory reference values

C1‑INH antigenic level< 50% of normal (baseline), as documented by laboratory reference values

C4 levelBelow laboratory lower limit of normal (single measurement)

Berinert/Cinryze prophylaxis dose (age ≥12)Up to 2,500 units (not exceeding 100 units/kg), IV, no more frequently than twice weekly; doses separated by ≥ 3 days

Berinert/Cinryze prophylaxis dose (age <12)Up to 1,000 units, IV, no more frequently than twice weekly; doses separated by ≥ 3 days

Berinert/Cinryze acute doseUp to 20 IU/kg, IV, no more frequently than once daily

Ruconest acute doseUp to 4,200 units (not exceeding 50 units/kg), IV, no more frequently than twice daily

Defined Terms

Definitions

HAEHereditary angioedema

C1‑INH antigenic levelMeasured concentration of C1 esterase inhibitor protein; policy uses <50% of normal as threshold

C1‑INH functional levelFunctional activity of C1 esterase inhibitor; policy uses <50% of normal as threshold

Non-Covered Product CriteriaEmployer Group and Individual & Family Plan specific exclusions listing age <18, current receipt of the product, or requirement to document failure/contraindication/intolerance to icatibant (Sajazir) as criteria for non-coverage

Policy Changes

2025-01-15clarifiedLatest

Annual revision performed with no criteria changes.

Policy Summary

PayerCigna

PolicyIntravenous C1 Esterase Inhibitors (Berinert, Cinryze, Ruconest) for Hereditary Angioedema (HAE)

Policy CodePolicy IP0315

Change TypeAnnual revision — no criteria changes

Effective DateJan 15, 2025

Next Review Date

SourceLink

On This Page

Medication is prescribed by, or in consultation with, an allergist/immunologist

Non-Covered Product Criteria is met (see Employer Group / Individual & Family Plan Non-Covered Products and Criteria tables)

Dosing: up to 20 IU/kg, IV, no more frequently than once daily

Concomitant prophylactic therapy with listed agents is exclusionary

Medication is prescribed by, or in consultation with, an allergist/immunologist

Non-Covered Product Criteria is met (see Employer Group / Individual & Family Plan Non-Covered Products and Criteria tables)

Dosing: up to a maximum dose of 4,200 units (not exceeding 50 units/kg), IV, no more frequently than twice daily

Documentation of beneficial response since initiating therapy (e.g., decreased duration of attacks, quick onset of relief, complete resolution, or decreased frequency/severity)

Medication continues to be prescribed by, or in consultation with, an allergist/immunologist