Orladeyo (berotralstat) is FDA-approved for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older. HAE is a rare disease that causes swelling, pain and inflammation in various areas of the body including the face, hands, feet, throat, stomach, and bowels. HAE can be caused by a reduced amount or decreased function of C1 esterase inhibitor protein, a regulator of inflammatory pathways.

The recommended dosage for Orladeyo (berotralstat) is 150 mg taken orally once daily. It is available as 150 mg and 110 mg capsules because dosage may need to be adjusted for certain patients (e.g., with moderate or severe hepatic impairment, with chronic administration of P-glycoprotein or breast cancer resistance protein (BCRP) inhibitors, or with persistent gastrointestinal reactions). Alternatives for Orladeyo (berotralstat) include products such as Takhzyro, Haegarda, Cinryze, or Danazol.

NOTE: The Plan requires that members be unable to use, or have tried and failed preferred product(s) first. Requests for non-formulary medications are also subject to Medical Necessity Criteria for Non-Formulary Drugs (PG069).

Definitions

• "C1 inhibitor" refers to an enzyme that functions as a major anti-inflammatory protein in the body. People who have HAE have low levels of C1 inhibitor in their body.
• "C4" or "Complement 4" refers to an enzyme that is involved in the inflammatory response. Alterations in C1 inhibitor can result in low levels of C4 in people who have HAE.
• "Hereditary angioedema (HAE)" refers to a rare, inherited disease that causes swelling, pain and inflammation in various areas of the body including the face, hands, feet, throat, stomach, and bowels.

Medical Necessity Criteria for Initial Authorization

The Plan considers Orladeyo (berotralstat) medically necessary when ALL of the following are met:

1. Prescribed by or in consultation with an allergist, hematologist, immunologist, or other specialist experienced in the diagnosis and management of hereditary angioedema (HAE); AND
2. The member is 12 years of age or older; AND
3. Is being used for prevention of attacks of hereditary angioedema (HAE), confirmed by ONE of the following:
   • clinically appropriate low levels (as defined by the laboratory reference values) of BOTH:
     1. low complement C4 (either at baseline or during an attack); and
     2. low C1 esterase inhibitor (C1-INH) antigenic protein level (Type 1 HAE) OR functional level (Type 2 HAE); or
   • Documented normal or near normal C4, C1-INH antigen, and C1-INH function AND ONE of the following:
     1. Demonstration of a mutation (e.g., in the factor XII, plasminogen, angiopoetin-1, or kininogen gene) associated with HAE; or
     2. A positive family history of recurrent angioedema and documented lack of efficacy of high-dose antihistamine therapy (e.g., cetirizine at 40 mg/day or the equivalent); AND
4. The member has a documented history of moderate or severe attacks of hereditary angioedema (e.g., airway swelling, severe abdominal pain, facial swelling, nausea and vomiting, painful facial distortion); AND
5. Dosage is within the recommended limit of 150 mg (taken orally) once daily; AND
6. Chart documentation and supporting laboratory test results are provided for review to substantiate the above listed requirements.

If the above prior authorization criteria are met, Orladeyo (berotralstat) will be approved for 6 months.

Medical Necessity Criteria for Reauthorization:

Reauthorization for 12 months will be granted if BOTH of the following are met:

1. the member still meets all applicable initial criteria; AND
2. chart documentation shows the member has experienced a positive clinical response to therapy as evidenced by ONE of the following compared to baseline (prior to starting prophylaxis therapy):
   • At least a (≥) 50% reduction in frequency of acute HAE attacks; or
   • Reduction in severity, duration, or need for rescue medication of acute HAE attacks.

Experimental or Investigational / Not Medically Necessary:

Orladeyo (berotralstat) for any other indication is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven.

References

1. Busse, PJ, Christensen, SC, et al. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema.The Journal of Allergy and Clinical Immunology: In Practice. 2021; 9(1):132-150. https://doi.org/10.1016/j.jaip.2020.08.046.
2. Fijen LM, Riedl MA, Bordone L, et al. Inhibition of Prekallikrein for Hereditary Angioedema. N Engl J Med 2022; 386:1026.
3. Jose J, Zacharias J, Craig T. Review of select practice parameters, evidence-based treatment algorithms, and international guidelines for hereditary angioedema. Clinical Reviews in Allergy and Immunology 2016;51(2):193-206. DOI: 10.1007/s12016-016-8546-7.
4. Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema: the 2017 revision and update. Allergy. 2018;73(8):1575-1596. doi:10.1111/all.13384
5. Mayoclinic.org. C1 inhibitor. 2021. Available at: https://www.mayoclinic.org/drugs-supplements/c1-esterase-inhibitor-recombinant-intravenous-route/description/drg-20110256. Accessed 23 Feb 2021.
6. Orladeyo (berotralstat) [prescribing information]. Durham, NC: BioCryst Pharmaceuticals Inc; March 2022.
7. Siles, R. Hereditary Angioedema. Published April 2017. Available at: https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/allergy/hereditary-angioedema/. Accessed 24 Feb 2021.