RUCONEST, C1 Esterase Inhibitor (Recombinant) BERINERT, C1 Esterase Inhibitor (Human) HAEGARDA, C1 Esterase Inhibitor (Human) CINRYZE, C1 Esterase Inhibitor (Human) Form

The following are C1 esterase inhibitors requiring prior authorization: human C1 esterase inhibitor (Berinert®, Cinryze®, Haegarda®) and recombinant C1 esterase inhibitor (Ruconest®) ____

• These criteria do NOT apply to California Commercial Exchange Plans. Requests for California Commercial Exchange Plans should be reviewed using HIM.PA.170. FDA Approved Indication(s) C1 esterase inhibitors are indicated:
  • For the treatment of acute abdominal, facial, or laryngeal hereditary angioedema (HAE) attacks in adult and pediatric patients [Berinert only] • For the treatment of acute attacks in adult and adolescent patients with HAE [Ruconest only] • For the routine prophylaxis against angioedema attacks in adults, adolescents, and pediatric patients (6 years of age and older) with HAE [Cinryze only] • For routine prophylaxis to prevent HAE attacks in patients 6 years of age and older [Haegarda only] Limitation(s) of use:
  • The safety and efficacy of Berinert for prophylactic therapy have not been established. • Effectiveness of Ruconest was not established in HAE patients with laryngeal attacks. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
  It is the policy of health plans affiliated with Centene Corporation® that Berinert, Cinryze, Haegarda, and Ruconest are medically necessary when the following criteria are met:
  I. Initial Approval Criteria
  A. Hereditary Angioedema* (must meet all):

  • These criteria do NOT apply to California Commercial Exchange Plans. Requests for California Commercial Exchange Plans should be reviewed using HIM.PA.170.
    1. Diagnosis of HAE confirmed by a history of recurrent angioedema and one of the following (a or b): a. Low C4 level and low C1-INH antigenic or functional level (see Appendix D); Page 1 of 10

  CLINICAL POLICY C1 Esterase Inhibitors b. Normal C4 level and normal C1-INH levels, and at least one of the following (i or ii): i. Presence of a mutation associated with the disease (see Appendix D); ii. Family history of angioedema and documented failure of high-dose antihistamine therapy (i.e., cetirizine 40 mg/day or equivalent) for at least 1 month or an interval expected to be associated with 3 or more attacks of angioedema, whichever is longer;

  2. Prescribed by or in consultation with a hematologist, allergist, or immunologist;
  3. Members meets one of the following (a, b, or c):
     a. Age ≥ 5 years for Berinert;
     b. Age ≥ 6 years for Cinryze or Haegarda; c. Age ≥ 13 years for Ruconest;
  4. Member meets one of the following (a, b, or c): a. For treatment of acute HAE attacks, request does not exceed 4 doses per month and meets one of the following (i or ii): i. Request is for Berinert; ii. Request is for Ruconest, and member does not experience laryngeal attacks; b. For long-term prophylaxis of HAE attacks, both of the following (i and ii): i. Request is for Cinryze or Haegarda; ii. Member experiences more than one severe event per month OR is disabled more than five days per month OR has a history of previous airway compromise; c. For short-term prophylaxis of HAE attacks, both of the following (i and ii): i. Member requires major dental work or surgical procedure; ii. Request does not exceed 2 doses per procedure;
  5. If request is for treatment of acute HAE attacks and member is age ≥ 18 years, failure of icatibant (generic Firazyr®), unless contraindicated or clinically significant adverse effects are experienced; Prior authorization may be required for icatibant
  6. If request is for long-term prophylaxis of HAE attacks, failure of Haegarda, unless contraindicated or clinically significant adverse effects are experienced;
  7. Member is not using the requested product in combination with another FDA- approved product for the same indication (e.g., using both Berinert and Firazyr for acute HAE attacks or using a combination of Cinryze, Haegarda, Orladeyo™, and/or Takhzyro™ for long-term prophylaxis of HAE attacks);
  8. Dose does not exceed one of the following (a, b, c, or d): a. Berinert: 20 IU/kg of body weight per single dose, up to 2 doses administered in a 24-hour period; b. Cinryze: 2,000 units (4 vials) every 3 to 4 days; c. Haegarda: 60 IU/kg of body weight per dose twice weekly; d. Ruconest: 4,200 IU per single dose, up to 2 doses administered in a 24-hour period. Approval duration:
     Short-term prophylaxis: 4 weeks (no more than 2 doses per procedure) Treatment of acute attacks: Up to 4 doses per month Medicaid – 6 months
     Page 2 of 10

  CLINICAL POLICY C1 Esterase Inhibitors Commercial – 6 months or to the member’s renewal date, whichever is longer Long-term prophylaxis: Medicaid – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):

  1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial and CP.PMN.16 for Medicaid; or
  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial and CP.PMN.53 for Medicaid.
     II. Continued Therapy
     A. Short Term Prophylaxis of Hereditary Angioedema Attacks
  3. Re-authorization is not permitted. Members must meet the initial approval criteria. Approval duration: Not applicable B. All Other Indications in Section I (must meet all):
  4. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
  5. Member is responding positively to therapy (e.g., if Cinryze or Haegarda are requested for long-term prophylaxis, member has demonstrated a reduction in attacks from baseline, or request is for a dose increase);
  6. Member is not using the requested product in combination with another FDA- approved product for the same indication (e.g., using both Berinert and Firazyr for acute HAE attacks or using a combination of Cinryze, Haegarda, Orladeyo, and/or Takhzyro for long-term prophylaxis of HAE attacks);
  7. For treatment of acute attacks, request does not exceed 4 doses per month;
  8. If request is for a dose increase, new dose does not exceed one of the following (a, b, c, or d): a. Berinert: 20 IU/kg of body weight per single dose, up to 2 doses administered in a 24-hour period; b. Cinryze: 2,000 units (4 vials) every 3 to 4 days; c. Haegarda: 60 IU/kg of body weight per dose twice weekly; Page 3 of 10

  CLINICAL POLICY C1 Esterase Inhibitors d. Ruconest: 4,200 IU per single dose, up to 2 doses administered in a 24-hour period. Approval duration:
  Treatment of acute attacks: Up to 4 doses per month Medicaid – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer Long-term prophylaxis: Medicaid – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Other diagnoses/indications (must meet 1 or 2):

  1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial and CP.PMN.16 for Medicaid; or
  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial and CP.PMN.53 for Medicaid.
     III. Diagnoses/Indications for which coverage is NOT authorized:
     A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial and CP.PMN.53 for Medicaid or evidence of coverage documents.
     IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key C1-INH: C1 esterase inhibitor C4: complement component 4 FDA: Food and Drug Administration HAE: hereditary angioedema HAE-nl-C1INH: hereditary angioedema with normal C1 inhibitor Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
     Drug Name Dosing Regimen Dose Limit/ Maximum Dose 40 mg/day (off- label) cetirizine 40 mg/day (off-label) Typical dosing range (mg/day): 10 mg/day Page 4 of 10

  CLINICAL POLICY C1 Esterase Inhibitors Drug Name Dosing Regimen icatibant (Firazyr®) US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema Treatment of acute HAE attacks: 30 mg SC in the abdominal area; if response is inadequate or symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 hours. Dose Limit/ Maximum Dose 90 mg/24 hours Do not administer more than 3 injections in 24 hours. Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Ruconest: known or suspected allergy to rabbits and rabbit derived products o Ruconest, Berinert, Cinryze, Haegarda: history of immediate/life-threatening hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations • Boxed warning(s): none reported Appendix D: General Information
  • Diagnosis of HAE: o There are two classifications of HAE: HAE with C1-INH deficiency (HAE-C1INH, further broken down into Type 1 and Type II) and HAE with normal C1-INH (also known as HAE-nl-C1INH). HAE-nl-C1INH was previously referred to as type III HAE, but this term is obsolete and should not be used. o In both Type 1 (~85% of cases) and Type II (~15% of cases), C4 levels are low. C1- INH antigenic levels are low in Type I while C1-INH functional levels are low in Type II. Diagnosis of Type I and II can be confirmed with laboratory tests. Reference ranges for C4 and C1-INH levels can vary across laboratories (see below for examples); low values confirming diagnosis are those which are below the lower end of normal. Laboratory Test & Reference Range C4 Quest Diagnostics Mayo Clinic 14-40 mg/dL LabCorp C1-INH, antigenic 19-37 mg/dL C1-INH, functional Normal: > 67% Equivocal: 41-67% Abnormal: < 41% 13-57 mg/dL (age- and gender- specific ranges) 21-39 mg/dL Normal: ≥ 68% Equivocal: 41-67% Abnormal: ≤ 40% 10-38 mg/dL (age- and gender- specific ranges) 21-39 mg/dL Normal: > 67% Equivocal: 41-67% Abnormal: < 41% o HAE-nl-C1INH, on the other hand, presents with normal C4 and C1-INH levels. Some patients have a known associated mutation, while others have no identified Page 5 of 10

  CLINICAL POLICY C1 Esterase Inhibitors genetic indicators. HAE-nl-C1INH is very rare, and there are no laboratory tests to confirm the diagnosis; mutations in 6 genes causing HAE-nl-C1INH have been identified:
  Identified Genes Associated with Mutations in HAE-nl-C1INH F12 ANGPT1 PLG KNG1 MYOF HS3ST6 • HAE attack triggers may include minor trauma (such as dental procedures). Short-term prophylaxis may be indicated before invasive medical, surgical, or dental procedures. Busse et al recommend that a single dose of 20 units/kg of plasma-derived C1 inhibitor can be given 1 to 12 hours before the stressor. On-demand treatment should also be available in the event of delayed swelling in the wake of the procedure. V. Dosage and Administration
  Drug Name human C1 esterase inhibitor (Berinert) human C1 esterase inhibitor (Haegarda) Indication Treatment of acute HAE attacks Prophylaxis against HAE attacks human C1 esterase inhibitor (Cinryze) Prophylaxis against HAE attacks recombinant C1 esterase inhibitor (Ruconest) Treatment of acute HAE attacks Maximum Dose Based on weight, 20 IU/kg/dose Based on weight, 60 IU/kg/dose Age 6-11 years:
  1,000 units every 3-4 days Age ≥ 12 years: 2,000 units (not exceeding 80 units/kg) every 3-4 days
  4,200 units/dose; up to 2 doses within a 24-hour period Dosing Regimen 20 IU/kg body weight IV 60 IU/kg body weight SC twice weekly (every 3 or 4 days) Age 6-11 years: 500 units IV every 3-4 days Age ≥ 12 years: 1,000 units IV every 3-4 days Weight < 84 kg: 50 units/kg IV Weight ≥ 84 kg: 4,200 units IV May administer a second dose if symptoms persist. VI. Product Availability
  Drug Name human C1 esterase inhibitor (Berinert) Availability Vial with powder for reconstitution: 500 IU Page 6 of 10

  CLINICAL POLICY C1 Esterase Inhibitors Drug Name human C1 esterase inhibitor (Haegarda) human C1 esterase inhibitor (Cinryze) recombinant C1 esterase inhibitor (Ruconest) Availability Vial with powder for reconstitution: 2,000 IU, 3000 IU Vial with powder for reconstitution: 500 units Vial with powder for reconstitution: 2,100 units VII.