Hereditary Angioedema (HAE)

POLICY NUMBER

L.5.01.434

Berinert (human c1 esterase inhibitor)

Cinryze (human c1 esterase inhibitor)

Firazyr (icatibant acetate)

Haegarda (human c1-esterase inhibitor)

Kalbitor (ecallantide)

Orladeyo (berotralstat)

Ruconest (recombinant c1-esterase inhibitor)

Takhzyro (lanadelumab-flyo)

Please perform a formulary drug search on your patient’s member ID to ensure the prescription drug is covered under their benefit plan. The medication(s) in this medical policy may not be covered under a specific member’s benefit plan.

DESCRIPTION

Hereditary angioedema (HAE) is a rare autosomal dominant disorder estimated to affect 1 in 60,000 people and is 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. Minor trauma or stress may trigger an attack, but swelling often occurs without a known trigger. The most common forms of HAE (types I and II) are caused by deficiency or dysfunction in C1 inhibitor (C1-INH).

For the majority of patients, the disease first presents in childhood or adolescence, and attack frequency usually increases after puberty. Many HAE attacks involve only one site at a time, although multilocational attacks may also occur. HAE attacks are always self-limited, lasting two to five days, and range in severity from inconvenient cutaneous swelling to life-threatening airway edema. The frequency and duration of attacks vary greatly among people with hereditary angioedema, even among people in the same family.

Once HAE attacks have begun, they generally continue throughout the patient’s life, although the frequency of attacks can be dramatically reduced by therapy. Early treatment of HAE attacks has been shown to result in improved efficacy. All of the first-line therapies for HAE are likely to be effective if given in the first few hours of the angioedema attack. First-line therapies for acute attacks include Berinert (human c1-esterase inhibitor), Firazyr (icatibant), Kalbitor (ecallantide), and Ruconest (recombinant c1-esterase inhibitor). In patients with frequent or severe episodes of angioedema, long-term prophylaxis may be required to maintain an acceptable quality of life. Guidelines suggest that the decision to initiate long-term prophylaxis be individualized based on attack frequency, comorbidities, patient preferences, and access to emergency care. Cinryze (human c1-esterase inhibitor), Haegarda (human c1-esterase inhibitor), Takhzyro (lanadelumab-flyo), and Orladeyo (berotralstat) are first-line therapies for long-term prophylaxis and are given to decrease the number, severity, and length of HAE attacks.

POLICY

Prior authorization is required.

The use of samples by an individual will not be considered current or stable therapy to satisfy Medical Policy requirements.

 Initial Criteria

Icatibant, Berinert, and/or Haegarda may be considered medically necessary when ALL of the following criteria are met:

1. ONE of the following:

   1. The individual is ≥18 years of age and the request is for Icatibant for acute treatment;

   2. The individual is <18 years of age and the request is for Berinert (human c1-esterase inhibitor) for acute treatment;

   3. The individual is 6 years of age or older and the request is for Haegarda (human c1-esterase inhibitor) for prophylactic treatment;

2. The individual has a diagnosis of Type I or Type II hereditary angioedema (HAE) evidenced by ONE of the following:

   1. BOTH of the following (there must be TWO separate low measurements, at least one month apart, for each test defined as below the testing laboratory’s lower limit of the normal range):

      1. Low Serum complement factor 4 (C4) level;

      2. EITHER Low C1-INH antigenic level OR Low C1-INH functional level;

   2. The individual has a mutation in the C1INH gene altering protein synthesis and/or function;

3. Medications known to cause angioedema (i.e. ACE-Inhibitors, estrogens, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs) have been evaluated and discontinued when appropriate;

4. ONE of the following:

   1. The request is for Berinert (human c1-esterase inhibitor) or icatibant and BOTH of the following:

      1. The requested agent will be used to treat acute HAE attacks;

      2. The individual is receiving only ONE agent indicated for treatment of acute HAE attacks;

   2. The request is for Haegarda (human c1-esterase inhibitor) and ALL of the following:

      1. The requested agent will be used for prophylaxis against HAE attacks;

      2. The individual has a history of at least 2 acute severe (e.g. swelling of the throat, incapacitating abdominal or cutaneous swelling) attacks per month;

5. The prescriber is a specialist or has consulted with a specialist in an area of the individual’s diagnosis (i.e., allergist, immunologist);

6. The individual does not have any FDA-labeled contraindication(s) to therapy with the requested agent;

7. ONE of the following:

   1. The request is for acute treatment and ONE of the following:

      1. The dose is within the quantity limit (allows for 2 acute attacks per month);

      2. The quantity (dose) requested is greater than the quantity limit and prescriber has submitted documentation (e.g. frequency of attacks within the past 3 months has been >2 attacks per month) in support of therapy with a higher quantity which has been reviewed and approved;

   2. The request is for prophylactic treatment and ONE of the following:

      1. The dose is within the FDA labeled dose range AND within the quantity limit;

      2. The quantity (dose) requested is greater than the quantity limit and prescriber has submitted documentation in support of therapy with a higher quantity which has been reviewed and approved.

Length of Approval:  6 months

Renewal Criteria

The requested agent may be approved for RENEWAL when ALL of the following criteria are met:

1. The individual has been previously approved for therapy with the requested agent through BCBSMS PA process;

2. ONE of the following:

   1. BOTH of the following:

      1. The requested agent was initially approved for acute treatment of HAE attacks;

      2. The individual is receiving only ONE agent indicated for treatment of acute HAE attacks;

   2. The requested agent was initially approved for prophylaxis of HAE attacks;

3. ONE of the following:

   1. The requested agent is for acute treatment of HAE attacks and BOTH of the following:

      1. The prescriber has submitted documentation that the individual continues to have acute HAE attacks;

      2. The prescriber has communicated with the individual regarding frequency and severity of attacks and has verified that the individual does not have >1 month supply (sufficient for 2 acute attacks) currently on-hand;

   2. The requested agent is for prophylaxis of HAE attacks AND the individual has had a documented decrease in the frequency of acute attacks from baseline (prior to treatment);

4. The individual does not have any FDA-labeled contraindication(s) to therapy with the requested agent;

5. ONE of the following:

   1. The request is for acute treatment and ONE of the following:

      1. The dose is within the quantity limit (allows for 2 acute attacks per month);

      2. The quantity (dose) requested is greater than the quantity limit and prescriber has submitted documentation (e.g. frequency of attacks within the past 3 months has been >2 attacks per month) in support of therapy with a higher quantity which has been reviewed and approved;

   2. The request is for prophylactic treatment and ONE of the following:

      1. The dose is within the FDA labeled dose range AND within the quantity limit;

      2. The quantity (dose) requested is greater than the quantity limit and prescriber has submitted documentation in support of therapy with a higher quantity which has been reviewed and approved.

Length of Approval: 12 months

 Cinryze (human c1-esterase inhibitor), Kalbitor (ecallantide), Orladeyo (berotralstat), Ruconest (recombinant c1-esterase inhibitor), and Takhzyro (lanadelumab-flyo) are considered not medically necessary as other formulary alternatives are covered by the Plan for both acute and prophylactic treatment of HAE attacks.

Services related to delivery and/or administration of a medication which have not been approved through the BCBSMS PA review process will be considered not medically necessary.

POLICY EXCEPTIONS

State Health Plan (State and School Employees) Participants

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

BCBSMS may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

BCBSMS determines individual medication trial and adherence by a review of pharmacy claims data over the preceding twelve months. Additional information may be requested on a case-by-case basis to allow for proper review. If individual is new to BCBSMS and pharmacy records are needed to confirm medication trials and adherence, it is the responsibility of the individual and/or requesting provider to obtain said records and to submit them to BCBSMS upon request. Medical records from the provider that list previously prescribed medications will not be sufficient to show medication trials or adherence.

POLICY HISTORY

04/01/2012: New policy added.

01/07/2013: Added the following new 2013 CPT code to the Code Reference section: J1744.

04/02/2014: Added the generic name for each brand name in the policy subtitle. Second policy statement revised to remove “only” from the statement. It previously stated that Berinert®, Cinryze®, and Kalbitor® should only be administered under the supervision of a healthcare professional; therefore, these medications are not appropriate for use in the home care setting and are not prior authorized.

08/28/2015: Medical policy revised to add ICD-10 codes. Removed HCPCS code J3590 from the Covered Codes table.

05/26/2016: Policy number L.5.01.434 added. Policy Guidelines updated to add medically necessary and investigative definitions.

11/01/2016: Approved by Pharmacy & Therapeutics (P&T) Committee.

08/01/2017: Policy description updated regarding FDA approved indications and quantity limits for Berinert®, Cinryze®, Firazyr®, Kalbitor®, and Ruconest®. Policy section re-written to add approval criteria for Berinert, Firazyr, Kalbitor, Ruconest, and Cinryze. Prior authorization is required. Policy Exceptions updated to state that prior authorization is not required for SHP (State and School Employees). However, it will be reviewed for medical necessity based on medical policy guidelines. Sources section updated. Code Reference section updated to add J0596. Removed the Investigational Codes table and added HCPCS codes J0597, J0598, and J1290 as covered, effective 08/01/2017.

08/15/2017: Policy reviewed and approved by Pharmacy & Therapeutics (P&T) Committee.

12/22/2017: Code Reference section updated to add new 2018 HCPCS code C9015.

07/01/2018: Policy reviewed and approved by Pharmacy & Therapeutics (P&T) Committee. Policy description updated to add indications for Haegarda®. Policy statements regarding prophylaxis treatment updated to include Haegarda®. Revised policy statement to state that Berinert, Firazyr, Kalbitor, Ruconest, Cinryze, and Haegarda are considered not medically necessary for all other indications. Sources updated.

12/19/2018: Code Reference section updated to add new HCPCS code J0599, effective 01/01/2019.

08/17/2021: Policy reviewed and approved by Pharmacy & Therapeutics (P&T) Committee. Added drug names to the top of the policy. Policy description updated regarding hereditary angioedema and first-line therapies. Policy section updated to add that the use of samples by a Member will not be considered current or stable therapy for purposes of Medical Policy review. Revised initial and renewal policy statement criteria. Added the following statements: 1) Cinryze (human c1-esterase inhibitor), Kalbitor (ecallantide), Orladeyo (berotralstat), Ruconest (recombinant c1-esterase inhibitor), and Takhzyro (lanadelumab-flyo) are considered not medically necessary as other formulary alternatives are covered by the Plan for both acute and prophylactic treatment of HAE attacks. 2) Services related to delivery and/or administration of a medication which have not been approved through the BCBSMS PA review process will be considered not medically necessary. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity." Added information regarding BCBSMS requests for medical records. Sources updated. Code Reference section updated to remove deleted HCPCS code C9015. Added the following HCPCS codes to the Non-Covered Codes table: J0593, J0596, J0598, and J1290.

02/01/2023: Policy Exceptions updated to add the following: State Health Plan (State and School Employees): The prescription drug(s) in this medical policy may be covered under a prescription drug benefit plan administered by the State Health Plan’s Pharmacy Benefit Manager. Please perform a formulary drug search at https://www.dfa.ms.gov/cvs-caremark and submit any required Prior Authorization Requests for coverage determination to the Plan’s Pharmacy Benefit Manager. Services related to delivery and/or administration of a medication determined to be not medically necessary will also be considered not medically necessary. Services related to delivery and/or administration of a self-administered drug are not covered.

07/01/2023: Policy Exceptions updated regarding State Health Plan (State and School Employees) Participants.

06/27/2024: Policy updated to extend Length of Approval to 6 months.

10/01/2024: Policy reviewed and approved by the Pharmacy & Therapeutics (P&T) Committee. Policy language updated to change "member" to "individual." Medically necessary indications updated for individuals with a diagnosis of Type I or Type II hereditary angioedema and medications known to cause angioedema. Sources updated. Effective 12/01/2024.

09/09/2025: Policy reviewed by Pharmacy & Therapeutics (P&T) Committee; no changes to policy statement. Sources updated.

SOURCE(S)

1. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021 Jan;9(1):132-150.e3. doi: 10.1016/j.jaip.2020.08.046. Epub 2020 Sep 6. PMID: 32898710.

2. Berinert prescribing information. CSL Behring GmbH.

   September 2021. Last accessed July 2025.

3. Cinryze prescribing information. Takeda Pharmaceuticals America, Inc.

   December 2024. Last accessed July 2025.

4. Firazyr prescribing information. Takeda Pharmaceuticals America, Inc.

   January 2024. Last accessed July 2025.

5. Haegarda prescribing information. CSL Behring GmbH.

   February 2022. Last accessed July 2025.

6. Kalbitor prescribing information. Takeda Pharmaceuticals America, Inc.

   July 2025. Last accessed July 2025.

7. Orladeyo prescribing information. BioCryst Pharmaceuticals Inc.

   October 2024. Last accessed July 2025.

8. Ruconest prescribing information. Pharming Healthcare Inc.

   April 2020. Last accessed July 2025.

9. Takhzyro prescribing information. Takeda Pharmaceuticals America, Inc.

   February 2025. Last accessed July 2025.

10. Zuraw B, Farkas H. Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis.  In: UpToDate, Connor RF (Ed), Wolters Kluwer. Accessed July 2025.  Available at: https://www.uptodate.com/contents/hereditary-angioedema-due-to-c1-inhibitor-deficiency-pathogenesis-and-diagnosis

11. Zuraw B, Bork K. Hereditary angioedema with normal C1 inhibitor. In: UpToDate, Connor RF (Ed), Wolters Kluwer. Accessed July 2025. Available at:   https://www.uptodate.com/contents/hereditary-angioedema-with-normal-c1-inhibitor

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Non-Covered Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.