State and School Employees' Health Insurance Plan - Hereditary Angioedema (HAE)

POLICY NUMBER

S.5.01.434

Berinert (human c1-esterase inhibitor)

Cinryze (human c1-esterase inhibitor)

Kalbitor (ecallantide)

Ruconest (recombinant c1-esterase inhibitor)

Please perform a search of the State Health Plan Medical Drug Formulary for drugs administered and billed through the medical setting.

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. Therapies for acute attacks include Berinert (human c1-esterase inhibitor), Ekterly (sebetralstat), 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. Andembry (garadacimab-gxii), Cinryze (human c1-esterase inhibitor), Dawnzera (donidalorsen), Haegarda (human c1-esterase inhibitor), Takhzyro (lanadelumab-flyo), and Orladeyo (berotralstat) are therapies for long-term prophylaxis and are given to decrease the number, severity, and length of HAE attacks.

POLICY

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

Initial Criteria

Berinert (human c1-esterase inhibitor) may be considered medically necessary when ALL of the following criteria are met:

1. ONE of the following:

   1. The individual has a diagnosis of hereditary angioedema (HAE) due to C1INH deficiency [HAE-C1INH (Type 1 or Type 2)] evidenced by ONE of the following:

      1. The individual’s diagnosis has been confirmed with measurements of C1-INH protein level, C1-INH function level, and C4 level as follows:

         1. Type 1 HAE: Decreased quantities of C4 level, C1-INH protein level, and C1-INH function level; OR

         2. Type 2 HAE: Decreased quantities of C4 level and C1-INH function level (C1-INH protein level may be normal or elevated); OR

      2. The individual’s diagnosis has been confirmed by mutation in the C1-INH gene altering protein synthesis and/or function; OR

   2. The individual has a diagnosis of HAE with normal C1INH [HAE-nC1INH (previously known as Type 3 HAE)] evidenced by BOTH of the following:

      1. The individual has levels within the normal range for C1-INH protein level, C1-INH function level, and C4 level; AND

      2. ONE of the following:

         1. The individual’s diagnosis is associated with a mutation in ONE of the following genes:

            1. Coagulation factor FXII (mutation in F12);

            2. Plasminogen;

            3. Angiopoietin-1;

            4. Kininogen-1;

            5. Heparan sulfate 3-O-sulfotransferase 6 gene; OR

            6. Myoferlin gene; OR

         2. The individual has a diagnosis of HAE-unknown (responsible mutation has not yet been defined) that has been confirmed by an HAE specialist (medical records required);

2. 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;

3. The request is for treatment of acute HAE attacks and ALL of the following:

   1. ONE of the following:

      1. The individual is < 18 years of age; OR

      2. The individual is > 18 years and has tried and had an inadequate response, intolerance, or FDA-labeled contraindication to icatibant treatment;

   2. ONE of the following:

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

      2. The requested quantity (dose) exceeds the program quantity limit and there is support for therapy with a higher quantity for the requested indication (e.g., frequency of attacks within the past 3 months has been greater than 2 attacks per month); AND

   3. The requested agent will not be used in combination with another agent indicated for the treatment of acute HAE attacks;

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

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

Length of Approval: 12 months

Renewal Criteria

Berinert (human c1-esterase inhibitor) 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 review process;

2. The requested agent is for acute treatment of HAE attacks and ALL of the following:

   1. 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 will not be used in combination with another agent indicated for the treatment of acute HAE attacks; AND

   3. ONE of the following:

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

      2. The requested quantity (dose) exceeds the program quantity limit and there is support for therapy with a higher quantity for the requested indication (e.g., frequency of attacks within the past 3 months has been greater than 2 attacks per month);

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

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

Length of Approval: 12 months

Cinryze (human c1-esterase inhibitor), Kalbitor (ecallantide), 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 determined to be not medically necessary will also be considered not medically necessary.

POLICY EXCEPTIONS

State Health Plan (State and School Employees): Self-administered drugs 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 self-administered drug are not covered under the medical benefit.

POLICY GUIDELINES

Medical Policy Manual coverage guidelines should not be used in lieu of the Participant's specific benefit plan language outlined in the Mississippi's State and School Employees’ Life and Health Insurance Plan.

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 Participant'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 Participant'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 Participant, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to the Participant. When applied to the care of an Inpatient, it further means that services for the Participant's medical symptoms or conditions require that the services cannot be safely provided to the Participant 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 Participant 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 Participant is new to BCBSMS and pharmacy records are needed to confirm medication trials and adherence, it is the responsibility of the Participant 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

07/01/2023: New policy added.

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

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

04/01/2026: Policy description updated regarding therapies for acute attacks and to add quantity limits for Berinert. Medically necessary criteria for Berinert (human c1-esterase inhibitor) updated regarding diagnosis of hereditary angioedema. Length of approval for initial criteria changed from "6 months" to "12 months." Renewal criteria updated regarding requests for acute treatment of HAE attacks and prescriber requirements. Code Reference section updated to remove ICD-9 diagnosis code.

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. Kalbitor prescribing information. Takeda Pharmaceuticals America, Inc. July 2025. Last accessed July 2025.

5. Ruconest prescribing information. Pharming Healthcare Inc. April 2020. Last accessed July 2025.

6. 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

7. 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

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

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