058 Form

1

Pharmacy Medical Policy Drugs for the Treatment of Hereditary Angioedema (HAE)

Table of Contents: Prior Authorization Information Coverage Criteria
Description
Appendix Policy History
Coding Information References Endnotes

Policy Number: 058

Related Policies • BCBSA Reference Number: N/A • Medical Benefit Prior Authorization Medication List #034 • Quality Care Dosing guidelines may apply to the following medications and can be found in Medical Policy #621

Prior Authorization Information

Policy ☒ Prior Authorization ☐ Step Therapy ☒ Quality Care Dosing ☐ Administrative Reviewing Department Pharmacy Operations: Tel: 1-800-366-7778 Fax: 1-800-583-6289 To request for coverage: Providers may call, fax, or mail the attached form (Formulary Exception/Prior Authorization form) to the address below.
Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043
Tel: 1-800-366-7778 Fax: 1-800-583-6289

Individual Consideration for the atypical patient: Policy for requests that do not meet clinical criteria of this policy, see section labeled Individual Consideration
Policy Last Updated 3/15/2026 Pharmacy (Rx) or Medical (MED) benefit coverage ☒ Rx ☒ MED Policy applies to Commercial members with BCBSMA formulary:
• Managed Care (HMO/POS) • PPO/EPO
• Indemnity
• MEDEX with Rx plans • Managed Blue for Seniors Policy does NOT apply to: • Medicare Advantage
Provider Documentation Requirements: Documentation from the provider to support a reason preventing trial of formulary alternative(s) must include the name and strength of alternatives tried and failed (if alternatives were tried, including dates if available) and specifics regarding the treatment failure. Documentation to support clinical basis preventing switch to formulary alternative should also provide specifics around clinical reason. We may also use prescription claims records to establish prior use of formulary alternatives or to show if step therapy criteria has been met. We will require the provider to share additional information when prescription claims data is either not available or the medication fill history fails to establish use of preferred formulary medications or that step therapy criteria has been met.
Other documentation requirements, if any, are outlined in prior authorization criteria.

2 Please refer to the chart below for the formulary status/requirements of the medications affected by this policy:

Drug Formulary Status
Special Considerations Preferred Drugs C1 ESTERASE INHIBITORS Berinert (C1 Esterase Inhibitor [Human]) PA Cinryze (C1 Esterase Inhibitor [Human]) PA

Haegarda (C1 Esterase Inhibitor [Human]) PA

Ruconest (C1 Esterase Inhibitor [Human]) PA

KALLIKREIN INHIBITORS Ekterly (sebetralstat) PA

Kalbitor (ecallantide) PA

Takhzyro (lanadelumab-flyo) PA

Orladeyo (berotralstat) PA, QCD

SELECTIVE BRADYKININ B2 RECEPTOR ANTAGONISTS Icatibant PA Generic Firazyr Sajazir (icatibant) PA Generic Firazyr Non-Formulary, Non-Covered* Firazyr (icabitant) NFNC, PA

FACTOR XIIa INHIBITOR Andembry (garadacimab-gxii) PA

PA – Prior Authorization; NFNC – Non-formulary, Non-Covered; QCD (Quality Care Dosing – refer to Policy 621b)
Approval Length: 12 months, unless otherwise specified in Clinical Guideline Coverage Criteria

Clinical Guideline Coverage Criteria

INITIAL APPROVAL
Coverage may be considered MEDICALLY NECESSARY when ALL the following criteria are met. Diagnosis Hereditary Angioedema (acute attacks and prophylaxis) Applicable Medications • C1 Esterase Inhibitors: Berinert, Cinryze, Haegarda, Ruconest, • Kallikrein inhibitors: Ekterly, Kalbitor, Orladyo, Takhzyro
• Selective Bradykinin B2 Receptor Antagonists: icatibant, Firazyr (NFNC), Sajazir • Factor XIIa Inhibitor: Andembry Approval Length • Takhzyro: 6 months • All other medications: 12 months

1. Confirmed diagnosis of hereditary angioedema AND
2. The requested drug is prescribing according to the FDA label:

3 a. Acute Angioedema Attacks: Berinert, Ekterly, Firazyr, Icatibant, Kalbitor, Ruconest, or Sajazir OR a. Routine Prophylaxis of Angioedema Attacks: Andembry, Cinryze, Haegarda, Orladeyo, or Takhzyro

3. Patient is at the age consistent with FDA labeling of requested drug: a. Not Age Restricted: Berinert (for adults and pediatric patients as weight-based dosing) b. Age ≥ 2 years: Takhzyro c. Age ≥ 6 years: Cinryze, Haegarda d. Age ≥ 12 years: Andembry, Ekterly, Kalbitor, Orladeyo e. Age ≥ 13 years: Ruconest f. Age ≥ 18 years: Icatibant, Firazyr (NFNC), Sajazir AND

4. For Firazyr requests: previous treatment with Sajazir OR prior use of icatibant acetate injection .. CONTINUATION OF THERAPY
   Continued coverage may be considered MEDICALLY NECESSARY when all the following criteria are met Diagnosis Routine Prophylaxis of Angioedema Attacks Applicable Medications • C1 Esterase Inhibitors: Cinryze, Haegarda, • Kallikrein inhibitors: Orladyo, Takhzyro • Factor XIIa Inhibitor: Andembry Approval Length • Takhzyro: 6 months • All other medications: 12 months

5. The patient meets the criteria for initial approval AND
6. The patient has experienced a significant reduction in frequency of attacks (e.g., ≥ 50%) since starting treatment AND
7. The patient has reduced the use of medications to treat acute attacks since starting treatment AND

8. If the request is for Takhzyro, the drug is being dosed every 4 weeks or dosing every 4 weeks has been considered if the patient is well-controlled on therapy for more than 6 months

   CONTINUATION OF THERAPY Continued coverage may be considered MEDICALLY NECESSARY when all the following criteria are met Diagnosis Acute Angioedema Attacks Applicable Medications • C1 Esterase Inhibitors: Berinert, Ruconest • Selective bradykinin B2 Receptor Antagonists: icatibant, Firazyr (NFNC), Sajazir,
   • Kallikrein inhibitors: Ekterly, Kalbitor Approval Length: • Takhzyro: 6 months • All other medications: 12 months

9. The patient meets the criteria for initial approval

4 Description Hereditary angioedema (HAE) is a rare genetic disorder that results in repeated, unpredictable attacks that involve swelling in various and localized subcutaneous or mucosal parts of the body such as in the face, feet, hands, and airways at any age. This disorder impacts approximately one in 50,000 people in the United States. There are two categories of HAE treatment: on-demand therapy to manage acute angioedema attacks and prophylactic therapy to reduce the frequency and severity of attacks.

Per the international WAO/EAACI guidelines for the management of angioedema, treatment goals for HAE are to achieve complete control of the disease and improve patients’ lives. HAE attacks should be treated as soon as possible with intravenous C1 Esterase Inhibitors, icatibant, or ecallantide. Treatment selection for prophylaxis should be individualized, taking patient quality of life, disease activity, and failure to gain adequate control with on-demand therapy into consideration.

FDA Approved Indications: Andembry (garadacimab-gxii) is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. Berinert (C1 Esterase Inhibitor [Human]) is indicated for the treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adults and pediatric patients. Cinryze (C1 Esterase Inhibitor [Human]) is indicated for routine prophylaxis against angioedema attacks in adults, adolescents, and pediatric patients ≥6 years of age with HAE Ekterly (sebetralstat) is indicated for the treatment of acute attacks of hereditary angioedema in adult and pediatric patients ≥12 years of age Haegarda (C1 Esterase Inhibitor [Human]) is indicated for routine prophylaxis against angioedema attacks in adults and pediatric patients ≥6 years of age with HAE. Ruconest (C1 Esterase Inhibitor [Human]) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adult and adolescent patients. Kalbitor (ecallantide) is indicated for the treatment of acute attacks of hereditary angioedema in patients 12 years of age and older. Takhzyro (Lanadelumab-flyo) is indicated for the prevention of attacks of hereditary angioedema in adults and pediatric patients ≥2 years of age. Orladeyo (berotralstat) is indicated for the prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients ≥12 years of age. Icatibant is indicated for the treatment of acute attacks of hereditary angioedema. Sajazir (icatibant) is indicated for the treatment of acute attacks of hereditary angioedema. Firazyr (icabitant) is indicated for the treatment of acute attacks of hereditary angioedema.

Appendix

Forms To request prior authorization using the Massachusetts Standard Form for Medication Prior Authorization Requests (eForm), click the link below: https://www.bluecrossma.org/medical- policies/sites/g/files/csphws2091/files/acquiadam- assets/023%20E%20Form%20medication%20prior%20auth%20instruction%20prn.pdf OR
Print and fax, Massachusetts Standard Form for Medication Prior Authorization Requests #434

5 Formulary Status* All requests must meet the Prior Authorization requirement. For non-covered medications, the member must also have had a previous treatment failure with, or contraindication to, at least two covered formulary alternatives when available. See section on individual consideration for more information if you require an exception to any of these criteria requirements for an atypical patient.
Individual Consideration (for Atypical Patients) Our medical policies are written for most people with a given condition. Each policy is based on peer reviewed clinical evidence. We also take into consideration the needs of atypical patient populations and diagnoses.
If the coverage criteria outlined is unlikely to be clinically effective for the prescribed purpose, the health care provider may request an exception to cover the requested medication based on an individual’s unique clinical circumstances. This is also referred to as “individual consideration” or an “exception request.”
Some reasons why you may need us to make an exception include: therapeutic contraindications; history of adverse effects; expected to be ineffective or likely to cause harm (physical, mental, or adverse reaction).
To facilitate a thorough and prompt review of an exception request, we encourage the provider to include additional supporting clinical documentation with their request. This may include: • Clinical notes or supporting clinical statements; • The name and strength of formulary alternatives tried and failed (if alternatives were tried) and specifics regarding the treatment failure, if applicable; • Clinical literature from reputable peer reviewed journals; • References from nationally recognized and approved drug compendia such as American Hospital Formulary Service® Drug Information (AHFS-DI), Lexi-Drug, Clinical Pharmacology, Micromedex or Drugdex®; and • References from consensus documents and/or nationally sanctioned guidelines

Providers may call, fax or mail relevant clinical information, including clinical references for individual patient consideration, to:

Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043 Phone: 1-800-366-7778 Fax: 1-800-583-6289 Member cost share consideration For those drugs that may be covered under the pharmacy benefit, a higher non-preferred cost share may be applied if an exception request is approved for coverage of a non- preferred or a non-formulary/non-covered drug. Samples Requests based exclusively on the use of samples will not meet coverage criteria for exception. Additional clinical information demonstrating medical necessity of the desired medication must be submitted by the requesting prescriber for review. Specialty Blue Cross Blue Shield of Massachusetts (BCBSMA*) members (other than Medex®; Blue MedicareRx, Medicare Advantage plans that include prescription drug coverage) obtaining the medication from the Pharmacy benefit instead of the Medical benefit will be required to fill their prescriptions for medications listed as specialty at one of the providers in our retail specialty pharmacy network, see link below: Link to Specialty Pharmacy List

6 CPT Codes / HCPCs Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list. The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity: HCPCS Codes HCPCS codes: Code Description J0598
Injection, C-1 esterase inhibitor (human), Cinryze, 10 units
J0597 Injection, C-1 esterase inhibitor (human), Berinert, 10 units J1744 Injection, icatibant, 1 mg (Firazyr/Sajazir) J0599 Injection, c-1 esterase inhibitor (human), (Haegarda), 10 units J1290 Injection, ecallantide, 1 mg (Kalbitor) J0596 Injection, c-1 esterase inhibitor (recombinant), Ruconest, 10 units J0593 Injection, lanadelumab-flyo, 1 mg (Takhzyro) C9399 Unclassified drugs or biologicals (Andembry) J3590 Unclassified biologics (Andembry) The following ICD Diagnosis Codes are considered medically necessary when submitted with the HCPCS codes above if medical necessity criteria are met:
ICD-10 Diagnosis Codes ICD-10-CM Diagnosis codes: Code Description D84.1
Defects in the complement system

Policy History Date Action 3/15/2026 January P&T: Added Ekterly to the policy. Clarified pre-requisite criteria for Icatibant agents. 11/2025 September P&T: Andembry added to the policy. 9/15/2025 Creation of new medical policy to group existing HAE agents together that were previously housed in MP #033 and MP #049 to streamline.

References

1. Andembry [package insert]. Kankakee, IL: CSL Behring LLC.: 06/2025.
2. Berinert [package insert]. Kankakee, IL: CSL Behring LLC.: 09/2021.
3. Cinryze [package insert]. Amsterdam, Netherlands: Sanquin Plasma Products B.V.: 3/2022.
4. Ekterly [package insert]. Cambridge, MA: KalVista Pharmaceuticals, INC.: 07/2025.
5. Firazyr [package insert]. Lexington, MA: Shire Orphan Therapies LLC.: 11/2017.
6. Haegarda [package insert]. Kankakee, IL: CSL Behring LLC.: 01/2022.

7

7. Immunology: Hereditary Angioedema (HAE). IPD Analytics. https://secure.ipdanalytics.com/User/Pharma/RxStrategy/Page/207dfd44-c707-448d-b09e- d77def396dfc#section-group-718519.
8. Kalbitor [package insert]. Lexington, MA: Dyax Corp: 12/2024.
9. Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema – the 2021 revision and update. World Allergy Organization Journal. 2022;77:1961-1990.
10. Orladeyo [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc.: 12/2020.
11. Ruconest [package insert]. Bridgewater, NJ: Pharming Healthcare. 04/2020.
12. Takhzyro [package insert]. Lexington, MA: Dyax Corp.: 01/2025.