WHA
 

Hereditary Angioedema Agents

Indications for Prior Authorization

Berinert (C1 esterase inhibitor [Human])
  • For diagnosis of Acute treatment of Hereditary Angioedema (HAE)
    Indicated for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adult and adolescent patients.

    The safety and efficacy of Berinert for prophylactic therapy have not been established.

Cinryze (C1 esterase inhibitor [Human])
  • For diagnosis of Prophylaxis of Hereditary Angioedema (HAE)
    Indicated for routine prophylaxis against angioedema attacks in adults, adolescents and pediatric patients (6 years old and above) with HAE.

  • For diagnosis of Acute treatment of Hereditary Angioedema (HAE)
    Following treatment with nanofiltered C1 inhibitor concentrate (Cinryze) for an acute attack, the median time to response was 30 minutes in 82 patients with HAE. [4]

Firazyr (icatibant)
  • For diagnosis of Acute treatment of Hereditary Angioedema (HAE)
    Indicated for the treatment of acute attacks of HAE in adults 18 years of age and older.

Criteria

Cinryze

Prior Authorization

Length of Approval: When approved; no reauthorization required
For diagnosis of Prophylaxis of HAE attacks

  • Diagnosis of hereditary angioedema (HAE) [A]
    • AND
  • One of the following [A-D]:
    • Diagnosis has been confirmed by both of the following:
      • C4 level below the lower limit of normal
        • AND
      • C1 inhibitor (C1-INH) deficiency or dysfunction (Type I or II HAE) as documented by ONE of the following:
        • C1-INH antigenic level below the lower limit of normal
        • C1-INH functional level below the lower limit of normal
      OR
    • Diagnosis has been confirmed by both of the following:
      • Both of the following:
        • Normal C4 levels
        • Normal C1-INH levels (HAE-nl-C1INH previously referred to as HAE Type III)
        AND
      • One of the following [A]:
        • Presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation as detected by an FDA-approved test or a test performed at a facility approved by Clinical Laboratory Improvement Amendments (CLIA) [9]
        • Patient has recurrent angioedema attacks that are refractory to high-dose antihistamines (e.g., cetirizine) with a confirmed family history of recurrent angioedema
    AND
  • For prophylaxis against HAE attacks
    • AND
  • Not used in combination with other approved treatments for prophylaxis against HAE attacks
    • AND
  • Patient is 6 years of age or older
    • AND
  • Prescribed by or in consultation with one of the following: [E]
    • Immunologist
    • Allergist
Cinryze [off-label], icatibant

Prior Authorization

Length of Approval: When approved; no reauthorization required
For diagnosis of Treatment of acute HAE attacks

  • Diagnosis of hereditary angioedema (HAE) [A]
    • AND
  • One of the following [A-D]:
    • Diagnosis has been confirmed by both of the following:
      • C4 level below the lower limit of normal
        • AND
      • C1 inhibitor (C1-INH) deficiency or dysfunction (Type I or II HAE) as documented by one of the following:
        • C1-INH antigenic level below the lower limit of normal
        • C1-INH functional level below the lower limit of normal
      OR
    • Diagnosis has been confirmed by both of the following:
      • Both of the following:
        • Normal C4 level
        • Normal C1-INH levels (HAE-nl-C1INH previously referred to as HAE Type III)
        AND
      • One of the following [A]:
        • Presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation as detected by an FDA-approved test or a test performed at a facility approved by Clinical Laboratory Improvement Amendments (CLIA) [9]
        • Patient has recurrent angioedema attacks that are refractory to high-dose antihistamines (e.g., cetirizine) with a confirmed family history of recurrent angioedema
    AND
  • For the treatment of acute HAE attacks [F, 4]
    • AND
  • Not used in combination with other approved treatments for acute HAE attacks
    • AND
  • One of the following:
    • For Cinryze, patient is 6 years of age or older
    • For icatibant, patient is 18 years of age or older
    AND
  • Prescribed by or in consultation with one of the following: [E]
    • Immunologist
    • Allergist
Berinert

Prior Authorization

Length of Approval: When approved; no reauthorization required
For diagnosis of Treatment of acute HAE attacks

  • Diagnosis of hereditary angioedema (HAE) [A]
    • AND
  • One of the following [A-D]:
    • Diagnosis has been confirmed by both of the following:
      • C4 level below the lower limit of normal
        • AND
      • C1 inhibitor (C1-INH) deficiency or dysfunction (Type I or II HAE) as documented by ONE of the following:
        • C1-INH antigenic level below the lower limit of normal
        • C1-INH functional level below the lower limit of normal
      OR
    • Diagnosis has been confirmed by both of the following:
      • Both of the following:
        • Normal C4 level
        • Normal C1-INH levels (HAE-nl-C1INH previously referred to as HAE Type III)
        AND
      • One of the following:
        • Presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation as detected by an FDA-approved test or a test performed at a facility approved by Clinical Laboratory Improvement Amendments (CLIA) [9]
        • Patient has recurrent angioedema attacks that are refractory to high-dose antihistamines (e.g., cetirizine) with a confirmed family history of recurrent angioedema
    AND
  • For the treatment of acute HAE attacks
    • AND
  • Not used in combination with other approved treatments for acute HAE attacks
    • AND
  • Prescribed by or in consultation with one of the following: [E]
    • Immunologist
    • Allergist

  • Guideline ID
    GL-570214

  • Formulary
    ehb

  • Effective date
    Jul 1, 2026

  • P&T approval date
    Feb 17, 2009

P & T Revisions

2026-04-14, 2026-04-02, 2026-01-22, 2025-12-18, 2024-10-18, 2024-04-08, 2023-11-01, 2023-10-31, 2023-04-05, 2023-03-31, 2022-04-04, 2021-11-29, 2021-10-05, 2021-08-02, 2021-05-19, 2021-03-02, 2021-02-19, 2020-11-18, 2020-06-30, 2020-02-18, 2019-09-03

  1. Cinryze Prescribing Information. Takeda Pharmaceuticals U.S.A., Inc. Cambridge, MA. November 2024.
  2. Berinert Prescribing Information. CSL Behring, LLC. Kankakee, IL. September 2021.
  3. Firazyr Prescribing Information. Takeda Pharmaceuticals U.S.A., Inc. Cambridge, MA. January 2024.
  4. Micromedex Healthcare Series [internet database]. Greenwood Village (CO): Thomson Reuters (Healthcare) Inc. Updated periodically. Available at: http://www.thomsonhc.com/. Accessed March 30, 2026.
  5. Cicardi M, Zuraw B. Hereditary angioedema: Pathogenesis and diagnosis. UpToDate Web site. Available at: http://www.uptodate.com/. Accessed June 27, 2025.
  6. Busse PJ, Christiansen S, Riedl M, et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of hereditary angioedema. J Allergy Clin Immunol. 2020; 9(1):132-150.
  7. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update. Allergy Eur J Allergy Clin Immunol. 2022; 77(7):1961-1990.
  8. Zuraw B, Bork K, Saini S, Feldweg AM. Hereditary angioedema with normal C1 inhibitor. Wolters Kluwer. Available at: http:www.uptodate.com. Updated October 1, 2025. Accessed March 30, 2026.
  9. Christiansen SC, Banerji A, Bernstein JA, et al. Hereditary angioedema with normal C1 inhibitor: A quarter century of forward progress and persisting obstacles. J Allergy Clin Immunol Pract. 2025; 13(6):1300-1309.
  10. Zuraw BL, Bork K, Bouillet L, et al. Hereditary angioedema with normal C1 inhibitor: an Updated International Consensus Paper on diagnosis, pathophysiology, and treatment. Clinic Rev Allerg Immunol. 2025; 68: 24.
  11. Per clinical consult with an allergist, July 22, 2025.
  12. FDA/CDER. Briefing Document for Blood products Advisory Committee. Presented May 2, 2008. Available at: http://www.fda.gov/. Accessed July 30, 2019.
  1. HAE is a rare genetic disorder that can be broadly divided into two fundamental types: 1) HAE-C1INH (HAE Type I or Type II), which presents with a deficiency of C1-INH; 2) HAE-nl-C1INH (previously referred to as HAE Type III), a rare variant which presents with normal C1-INH levels. This condition is inherited in an autosomal dominant manner characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Diagnosis of Type I or Type II HAE requires laboratory testing to confirm low or abnormal levels of C1-inhibitor. HAE-nl-C1INH (previously referred to as HAE Type III) presents a diagnostic challenge given the current lack of a validated biochemical test to confirm diagnosis. Per HAE guidelines, when a diagnosis of HAE-nl-CINH is suspected based on normal C1-INH levels, diagnosis should be confirmed by a known mutation associated with the disease or a positive family history of recurrent angioedema with a lack of efficacy to high-dose antihistamine therapy. Confirmation that patients’ angioedema episodes are non-responsive to high-dose antihistamine therapy helps to rule out histaminergic angioedema, as HAE-nl-C1NH is bradykinin-mediated. [5, 6]
  2. When HAE is suspected based on the clinical presentation, appropriate testing includes measurement of the serum C4 level, C1INH antigenic level, and C1INH functional level. Low C4 plus low C1INH antigenic or functional levels are consistent with a diagnosis of HAE-C1INH. [6, 7]
  3. Due to the rarity of HAE-nl-C1INH, guidance for treatment is anecdotal. Generally, the treatment strategy for HAE-nl-C1INH follows that of HAE-C1INH, where both acute and prophylactic treatment options are utilized to prevent HAE attacks. [8-10]
  4. Per consult with allergist, it is clinically appropriate to include patients with HAE-nl-C1INH in criteria for both acute treatment and prophylactic therapies. [11]
  5. Includes immunologist and allergist specialties to ensure the requirement for proper diagnosing and assessing the severity of the symptoms. In the pivotal Cinryze trial, criteria for participation of long term prophylaxis included patients 9 years and older with documented HAE (based on: a low C4 level plus low C1 inhibitor antigenic level/or low C1 inhibitor functional level OR a known HAE causing mutation) AND a history of at least two HAE attacks per month. [1, 12]
  6. Following treatment with nanofiltered C1 inhibitor concentrate (Cinryze) for an acute attack, the median time to response was 30 minutes in 82 patients with hereditary angioedema (median number of attacks per patient, 3; range, 1 to 57 attacks) in an open-label extension trial (median follow-up of 11 months). Additionally, 93% of attacks responded within 4 hours after C1 inhibitor concentrate treatment. [4]
  • 2026-04-14: Annual Review 2026 - Added icatibant PA criteria. Added C4 diagnostic requirements and additional HAE-nl-C1INH-associated gene mutation options (i.e., myoferlin, HS3ST6). Background updates. Removed "NF" in guideline name.
  • 2026-04-02: PA Reduction Program - Updated PA criteria buckets with approval duration of no reauthorization required and removed reauthorization criteria buckets.
  • 2026-01-22: Updated EHB standalone guideline to contain covered products (Cinryze, Berinert) only. No clinical criteria changes.
  • 2025-12-18: no criteria changes, added IL statute operational note
  • 2024-10-18: update guideline
  • 2024-04-08: update guideline
  • 2023-11-01: Updated initial criteria. Added reauthorization criteria. Updated background.
  • 2023-10-31: update guideline
  • 2023-04-05: Annual review: Updated Takhzyro criteria age requirement. Added new 150 mg/mL syringe formulation of Takhzyro (GPI 8584204020E510) to existing Takhzyro criteria. Updated references and background/indications.
  • 2023-03-31: Updated GPIs
  • 2022-04-04: Added new Takhzyro GPI for prefilled syringe. Annual review: Updated background and references.
  • 2021-11-29: background update
  • 2021-10-05: Added Sajazir to GL and updated the embedded step for Firazyr to be a trial of one of the following: generic icatibant or Sajazir.
  • 2021-08-02: Addition of embedded step through generic icatibant for brand Firazyr only
  • 2021-05-19: Addition of EHB formulary to guideline, no changes to criteria
  • 2021-03-02: 2021: No changes
  • 2021-02-19: updated guideline to add criteria for newly approved drug Orladeyo to guideline. Updated existing criteria for both the prophylactic agents and acute treatment agents
  • 2020-11-18: Updated Haegarda indication section for expanded age indication; no criteria changes
  • 2020-06-30: Revised guideline to add new Berinert criteria.
  • 2020-02-18: 2020 Annual Review
  • 2019-09-03: Added generic Firazyr (icatibant) and updated background.