Pharmacy Prior Authorization Criteria

Hereditary Angioedema Agents - PA, NF

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. [3]

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.

Haegarda (C1 esterase inhibitor [Human])

• For diagnosis of Prophylaxis of Hereditary Angioedema (HAE)
  Indicated for routine prophylaxis to prevent HAE attacks in patients 6 years of age and older.

Kalbitor (ecallantide)

• For diagnosis of Acute treatment of Hereditary Angioedema (HAE)
  Indicated for treatment of acute attacks of HAE in patients 12 years of age and older.

Orladeyo (berotralstat)

• For diagnosis of Prophylaxis of Hereditary Angioedema (HAE)
  Indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.

  Limitations of Use: The safety and effectiveness of ORLADEYO for the treatment of acute HAE attacks have not been established. ORLADEYO should not be used for treatment of acute HAE attacks. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended due to the potential for QT prolongation.

Ruconest (C1 esterase inhibitor [Recombinant])

• For diagnosis of Acute treatment of Hereditary Angioedema (HAE)
  Indicated for the treatment of acute attacks in adult and adolescent patients with HAE.

  Limitation of Use: Effectiveness was not established in HAE patients with laryngeal attacks.

Takhzyro (lanadelumab-flyo)

• For diagnosis of Prophylaxis of Hereditary Angioedema (HAE)
  Indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 2 years and older.

Sajazir (icatibant)

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

Criteria

Cinryze, Haegarda, Orladeyo, Takhzyro

Prior Authorization (Initial Authorization)

Length of Approval: 12 Month(s)
For diagnosis of Prophylaxis of HAE attacks

• Diagnosis of hereditary angioedema (HAE) [A]
AND
• One of the following [A, E]:
• 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
AND
• Normal C1-INH levels (HAE-n1-C1INH previously referred to as HAE Type 3)
AND
• One of the following:
• Confirmed presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation
• 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 [3]
AND
• Not used in combination with other approved treatments for prophylaxis against HAE attacks
AND
• One of the following:
• Patient is 6 years of age or older (applies to Cinryze and Haegarda only)
• Patient is 12 years of age or older (applies to Orladeyo only)
• Patient is 2 years of age or older (applies to Takhzyro only)
AND
• One of the following:
• Trial and failure, contraindication or intolerance to one of the following: (applies to Cinryze only)
• Orladeyo
• Haegarda
• Takhzyro
OR
• For continuation of prior therapy (applies to Cinryze only)
AND
• Prescribed by or in consultation with one of the following: [B]
• Immunologist
• Allergist

Cinryze, Haegarda, Orladeyo, Takhzyro

Prior Authorization (Reauthorization)

Length of Approval: 12 Month(s)
For diagnosis of Prophylaxis of HAE attacks

• Patient demonstrates positive clinical response to therapy (e.g., reduction in the number or rate of HAE attacks while on therapy)
AND
• Not used in combination with other approved treatments for prophylaxis against HAE attacks

Cinryze [off-label], Brand Firazyr, Generic icatibant, Sajazir, Ruconest, or Kalbitor

Prior Authorization (Initial Authorization)

Length of Approval: 12 Month(s)
For diagnosis of Treatment of acute HAE attacks

• Diagnosis of hereditary angioedema (HAE) [A]
AND
• One of the following [A, E]:
• 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
AND
• Normal C1-INH levels (HAE-n1-C1INH previously referred to as HAE Type 3)
AND
• One of the following:
• Confirmed presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation
• 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 [3, C]
AND
• Not used in combination with other approved treatments for acute HAE attacks
AND
• One of the following:
• Patient is 6 years of age or older (applies to Cinryze only)
• Patient is 12 years of age or older (applies to Kalbitor only) [D]
• Patient is 13 years of age or older (applies to Ruconest only) [5]
• Patient is 18 years of age or older (applies to Brand Firazyr, generic icatibant, and Sajazir only)
AND
• Prescribed by or in consultation with one of the following: [B]
• Immunologist
• Allergist
AND
• Trial and failure or intolerance to generic icatibant (applies to brand Firazyr only):

Cinryze [off-label], Brand Firazyr, Generic icatibant, Sajazir, Ruconest, or Kalbitor

Prior Authorization (Reauthorization)

Length of Approval: 12 Month(s)
For diagnosis of Treatment of acute HAE attacks

• Patient demonstrates positive clinical response to therapy
AND
• Not used in combination with other approved treatments for acute HAE attacks

Berinert

Prior Authorization (Initial Authorization)

Length of Approval: 12 Month(s)
For diagnosis of Treatment of acute HAE attacks

• Diagnosis of hereditary angioedema (HAE) [A]
AND
• One of the following [A, E]:
• 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
AND
• Normal C1-INH levels (HAE-n1-C1INH previously referred to as HAE Type 3)
AND
• One of the following:
• Confirmed presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation
• 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 [3, C]
AND
• Not used in combination with other approved treatments for acute HAE attacks
AND
• One of the following:
• Trial and failure, contraindication, or intolerance to Ruconest
OR
• One of the following [5]:
• Patient is 12 years of age or younger
• Documentation that patient has history of laryngeal attacks
AND
• Prescribed by or in consultation with one of the following: [B]
• Immunologist
• Allergist

Berinert

Prior Authorization (Reauthorization)

Length of Approval: 12 Month(s)
For diagnosis of Treatment of acute HAE attacks

• Patient demonstrates positive clinical response to therapy
AND
• Not used in combination with other approved treatments for acute HAE attacks

Cinryze

Non Formulary

Length of Approval: 12 Month(s)
For diagnosis of Prophylaxis of HAE attacks

• Submission of medical records (e.g., chart notes) confirming diagnosis of hereditary angioedema (HAE) [A]
AND
• One of the following [A]:
• Submission of medical records (e.g., chart notes) documenting 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
• Submission of medical records (e.g., chart notes) documenting diagnosis has been confirmed by both of the following:
• Both of the following:
• Normal C4 level
AND
• Normal C1-INH levels (HAE-n1-C1INH previously referred to as HAE Type 3)
AND
• One of the following:
• Confirmed presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation
• 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 [3]
AND
• Not used in combination with other approved treatments for prophylaxis against HAE attacks
AND
• Patient is 6 years of age or older
AND
• One of the following:
• Paid claims or submission of medical records (e.g., chart notes) confirming a trial and failure, contraindication or intolerance to one of the following:
• Orladeyo
• Haegarda
• Takhzyro
OR
• Both of the following:
• Paid claims or submission of medical records (e.g., chart notes) confirming continuation of prior therapy, defined as no more than a 45-day gap in therapy
AND
• Patient demonstrates positive clinical response to therapy
AND
• Prescribed by or in consultation with one of the following: [B]
• Immunologist
• Allergist

Brand Firazyr

Non Formulary

Length of Approval: 12 Month(s)
For diagnosis of Treatment of acute HAE attacks

• Submission of medical records (e.g., chart notes) confirming diagnosis of hereditary angioedema (HAE) [A]
AND
• One of the following [A]:
• Submission of medical records (e.g., chart notes) documenting 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
• Submission of medical records (e.g., chart notes) documenting diagnosis has been confirmed by both of the following:
• Both of the following:
• Normal C4 level
AND
• Normal C1-INH levels (HAE-n1-C1INH previously referred to as HAE Type 3)
AND
• One of the following:
• Confirmed presence of a factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, or heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutation
• 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 [3, C]
AND
• Not used in combination with other approved treatments for acute HAE attacks
AND
• Patient is 18 years of age or older
AND
• Both of the following:
• Submission of medical records (e.g., chart notes) confirming the patient has experienced intolerance (e.g., allergy to excipient) with generic icatibant
AND
• Submission of medical records confirming generic icatibant has not been effective AND justification/rationale provided explaining how Brand Firazyr is expected to provide benefit when generic icatibant has not been shown to be effective despite having the same active ingredient
AND
• One of the following:
• Paid claims or submission of medical records (e.g., chart notes) confirming a trial and failure, contraindication or intolerance to all of the following:
• Berinert
AND
• Kalbitor
AND
• One of the following:
• Ruconest
OR
• Documentation that patient has history of laryngeal attacks
OR
• Both of the following:
• Paid claims or submission of medical records (e.g., chart notes) confirming continuation of prior therapy, defined as no more than a 45-day gap in therapy
AND
• Patient demonstrates positive clinical response to therapy
AND
• Prescribed by or in consultation with one of the following: [B]
• Immunologist
• Allergist

P & T Revisions

2025-01-08, 2024-07-19, 2024-03-05, 2024-02-02, 2023-11-03, 2023-10-02, 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

References

1. Cinryze Prescribing Information. Shire ViroPharma, Inc. Lexington, MA. February 2023.
2. Haegarda Prescribing Information. CSL Behring, LLC. Kankakee, IL. January 2022.
3. Micromedex Healthcare Series [internet database]. Greenwood Village (CO): Thomson Reuters (Healthcare) Inc. Updated periodically. Available at: http://www.thomsonhc.com/. Accessed July 30, 2019.
4. Berinert Prescribing Information. CSL Behring, LLC. Kankakee, IL. September 2021.
5. Ruconest Prescribing Information. Pharming Healthcare Inc. Bridgewater, NJ. April 2020.
6. Firazyr Prescribing Information. Shire Orphan Therapies LLC. Lexington, MA. October 2021.
7. Kalbitor Prescribing Information. Dyax Corp. Lexington, MA. November 2021.
8. FDA/CDER. Briefing Document for Blood products Advisory Committee. Presented May 2, 2008. Available at: http://www.fda.gov/. Accessed July 30, 2019.
9. Craig TJ, Levy RJ, Wasserman RL. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. Oct 2009;124(4):801-8.
10. Cicardi M, Zuraw B. Hereditary angioedema: Pathogenesis and diagnosis. UpToDate Web site. Available at: http://www.uptodate.com/. Accessed July 30, 2019.
11. Takhzyro Prescribing Information. Dyax Corp. Lexington, MA. February 2023.
12. Orladeyo Prescribing Information. BioCryst Pharmaceuticals, Inc. Durham, NC. March 2022.
13. Sajazir Prescribing Information. Cipla Ltd., India. May 2022.
14. 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. Available at: https://www.haea.org/assets/img/2020MAB_guidelines.pdf. Accessed June 26, 2024.
15. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update. European Journal of Allergy and Clinical Immunology. 10 January 2022. Available at: https://onlinelibrary.wiley.com/doi/10.1111/all.15214. Accessed June 26, 2024.
16. Zuraw B, Bork K, et. al. Hereditary angioedema with normal C1 inhibitor - UpToDate web site. Available at: http:www.uptodate.com/. Accessed June 24, 2024.

---

End Notes

1. HAE is a rare genetic disorder that can be broadly divided into two fundamental types: 1) HAE-C1INH (HAE Type 1 or Type 2), which presents with a deficiency of C1-INH; 2) HAE-n1-C1INH (previously referred to as HAE Type 3), 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 1 or Type 2 HAE requires laboratory testing to confirm low or abnormal levels of C1-inhibitor. HAE-n1-C1INH (previously referred to as HAE Type 3) presents a diagnostic challenge given the current lack of a validated biochemical test to confirm diagnosis. Per HAE guidelines, when a diagnosis of HAE-n1-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 [10, 14].
2. 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 attack per month. [1, 8] Berinert is approved for the treatment of acute attacks in patients who are 13 years and older. In the pivotal Berinert trial patients had laboratory-confirmed C1-inhibitor deficiency (type I or II HAE). [9]
3. 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 hr after C1 inhibitor concentrate treatment. [3]
4. Kalbitor carries a black box warning that states the following: "Anaphylaxis has been reported after administration of Kalbitor. Because of the risk of anaphylaxis, Kalbitor should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema (HAE). Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer Kalbitor to patients with known clinical hypersensitivity to Kalbitor." In 255 HAE patients treated with intravenous or subcutaneous Kalbitor in clinical studies, 10 patients (3.9%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous Kalbitor, 5 patients (2.7%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing. Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5.1%), rash (3.1%), and urticaria (2.0%). Patients should be observed for an appropriate period of time after administration of Kalbitor, taking into account the time to onset of anaphylaxis seen in clinical trials. In the Kalbitor HAE program, patients developed antibodies to ecallantide. Rates of seroconversion increased with exposure to ecallantide over time. Overall, 7.4% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 4.7% of patients. Anti-ecallantide and anti-Po pastoris IgE antibodies were also detected. While the long-term effects of antibodies to Kalbitor are not known, patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The manufacturer developed a Risk Evaluation and Mitigation Strategy (REMS) program consisting of a Medication Guide and Communication Plan to notify healthcare professionals of the risk of anaphylaxis and the need to distinguish signs and symptoms of anaphylaxis and HAE attack as they may overlap. The presence of the black box warning necessitating administration by a healthcare professional; development of antibodies to ecallantide that may predispose patients to higher risks of hypersensitivity reactions; and the requirement for a REMS program offer compelling evidence to warrant the continued inclusion of an age criterion. [7]
5. 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 [14, 15].

---

Revision History

• 2025-01-08: Removed Sajazir from NF criteria
• 2024-07-19: Annual review: Updated diagnostic criteria for all HAE types to confirm C4 level for both acute and prophylactic agents. Updated HAE Type 3 mutation criteria for both acute and prophylactic agents to add additional known mutations as options (myoferlin and heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene mutations). Merged Kalbitor criteria with other existing acute agents criteria – added existing Kalbitor age requirement to this section. Added Ruconest age requirement. Updated Cinryze NF criteria verbiage to align with standard language. Added NF criteria for Brand Firazyr, Sajazir. Updated references and background.
• 2024-03-05: update guideline
• 2024-02-02: update guideline
• 2023-11-03: Updated initial criteria. Added reauthorization criteria. Updated background. Drug-specific NF criteria updated to align with updates made to PA criteria.
• 2023-10-02: guideline update
• 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.

---