Coverage Policy Manual
Policy #: 2013032
Category: Pharmacy
Initiated: September 2013
Last Review: September 2018
  Hereditary Angioedema (HAE), Prophylaxis and Acute Treatment

Description:
Although urticaria and angioedema are common problems that affect nearly 20% of the population, HAE is a rare disorder. It accounts for approximately 2% of clinical angioedema cases and occurs in 1 per 50,000-150,000 population. HAE leads to 15,000-30,000 emergency department visits per year in the United States. HAE is clinically diagnosed by recurrent episodes of localized subcutaneous or submucosal edema lasting between 2-5 days. The most commonly involved areas included the skin,upper respiratory tract, oropharynx, and gastrointestinal tract. The disease can be functionally disabling and in some circumstances can be fatal.
 
Hereditary angioedema (HAE) is due to mutations within the C1-INH gene and is transmitted as an autosomal dominant trait. The gene for C1-INH (SERPING1) has been mapped to 11q12-q13.1. Approximately 450 different genetic mutations have been described in HAE, and a spontaneous mutation rate of 25% has been reported. The 2 variants of HAE related to C1-INH function are type I (85%) and type II (15%).
 
The primary mediator of swelling in HAE-1/2 is bradykinin. Bradykinin is a low molecular weight nonapeptide, which is generated when active plasma kallikrein cleaves high molecular weight kininogen (HMWK). Bradykinin is rapidly metabolized by endogenous metalloproteases including angiotensin-converting enzyme (ACE). Plasmakallikrein is activated from its inactive zymogen prekallikrein by the protease factor XII. Both, plasma kallikrein and factor XII are
inhibited by C1-INH.
 
There are several types of HAE. Two main types of HAE involve insufficient or defective C1-inhibitor (C1-INH) protein, which helps to regulate the flow of body fluids in and out of cells. This regulation plays a key role in HAE attacks. (http://www.haehope.com/about-hae/types-of-hae.html)
 
 HAE with deficient or dysfunctional C1-INH
A)  Type I HAE: Most patients (approximately 85%) have Type I HAE, which results from
insufficient production of the C1-inhibitor (C1-INH) protein.
 
· Low C1 esterase inhibitor (C1-INH level)
· Low C4 level
· Normal or low C1-INH function
 
B) Type II HAE: A minority of patients have this type of HAE, which is caused by production of
defective or dysfunctional C1-inhibitor (C1-INH) protein.
 
      • Normal or elevated C1-INH level
· Low C4 levels
· Low C1-INH function
 
HAE with Normal C1-INH (previously Type III HAE)
A third type of HAE, sometimes referred to as Type III, is extremely rare. Clinically, symptoms
of Type III HAE are the same as those of Type I and Type II; however, C1-inhibitor (C1-INH)
levels and function are normal in these patients.
 
· Normal C1-INH level
· Normal C1-INH functional assay
· C4 level may be elevated
· Factor XII mutation may be present or other rare mutations ANGPT1 (angiopoietin) or PLG (plasminogen)
 
Type I HAE is caused by mutations occurring in the SERPING1 gene, which result in either a truncated
or misfolded protein. This protein is not secreted efficiently, resulting in low antigenic and functional
plasma levels of a normal C1-INH protein. Even though one normal allele is present, less than 50% of
functional C1-INH is present. A possible explanation is that the normal C1-INH protein is downregulated,
and this is supported by the finding of decreased levels of C1-INH mRNA in patients with
HAE Half the normal level of C1-INH is believed to be insufficient to prevent attacks of angioedema.
 
Type II HAE is caused by mutations that involve the active site of exon 8. These mutations result in a
dysfunctional protein. Therefore, patients with type II HAE have normal or elevated antigenic levels of
a dysfunctional mutant protein together with reduced levels of the functional protein. C1-INH
deficiency allows autoactivation of C1, with consumption of C4 and C2.
 
HAE with mutation in the F12 gene (HAE-FXII), HAE with mutation in the angiopoietin-1 gene (HAE-ANGPTI), and HAE with mutation in the plasminogen gene (HAE-PLG) as well as some patients have HAE due to unknown mutations (HAE-UNK) all are considered as HAE with normal C1INH.
 
The diagnosis of HAE should is considered when a patient presents with a history of recurrent angioedema attacks with the following findings:
  1) A positive family history (although this may not be present in up to 25% of patients),
  2) Onset of symptoms in childhood/adolescence,
  3) Recurrent and painful abdominal symptoms,
  4) Occurrence of upper airway edema,
  5) Failure to respond to antihistamines, glucocorticoids, or epinephrine,
  6) Presence of prodromal signs or symptoms before swellings, and/or
  7) The absence of urticaria (wheals).
 
Coding
Effective January 01, 2019, there is a specific HCPCS code for  Haegarda:
 
J0599 Injection, c-1 esterase inhibitor (human), haegarda
  

Policy/
Coverage:
Effective June 1, 2018, Prior Approval is required for all HAE treatment regimens.  
 
Effective September 2018
 
All drugs administered for continued treatment of HAE with abnormal C1INH deficiency/defect (Type I and Type II HAE) will require Prior Approval (PA).  None of the below drugs is approved for HAE with Normal C1-INH (previously Type III HAE).
 
Primary coverage criteria are met when a diagnosis of hereditary angioedema is confirmed based on supportive clinical and physical findings combined with results of C4 and C1-INH antigenic and functional activity levels by current or historical testing on two separate occasions with demonstration in both results of either: a) low C4 and C1-INH protein (type 1 HAE) or b) low C4, normal C1-INH, and low functional C1-INH (type 2 HAE).*
 
*Low C4 level--C4 less than 14 mg/dL; normal range 14 to 40 mg/dL, or C4 below the lower limit of normal as defined by the laboratory performing the test.
 
Low C1-INH--(C1-INH) antigenic level (C1INH less than 19 mg/dL; normal range 19 to 37 mg/dL, or C1INH antigenic level below the lower limit of normal as defined by the laboratory performing the test.
 
Low C1-INH functional activity level-- functional C1INH less than 50 % or C1INH functional level below the lower limit of normal as defined by the laboratory performing the test.
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Treatment of  HAE Acute Attacks
 
The below agents meet member benefit certificate primary coverage criteria and are covered for use
in the treatment of acute moderate-severe episodes of established HAE with deficient or dysfunctional C1-INH (craniofacial, laryngeal, or gastrointestinal angioedema). Use is limited to one agent. Combination of below agents for treatment of acute attacks is not allowed.  Prior approval allows members to have sufficient medication for on-demand treatment of two attacks:
 
Plasma derived C1-INH (Berinert ), indicated for the treatment of acute abdominal, facial, or laryngeal hereditary angioedema (HAE) attacks in adult and pediatric patients,  requires all of the following criteria:
 
          • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as described above
          • Clinical evidence of angioedema with moderate to severe attacks
          • Age > 5 y/o
          • Use in treatment of acute attacks (not prophylaxis)
          • 20 units/kg of body weight for the treatment of a HAE acute attack of abdominal, facial, or laryngeal areas in adults or children, administered IV. . A vial contains 500 units.
 
Recombinant C1-INH (Ruconest) indicated for the treatment of acute attacks (including laryngeal edema) in adult and adolescent patients with hereditary angioedema (HAE)   Requires All of the following criteria be met:
 
          • Clinical evidence of angioedema with moderate to severe attacks.
          •  Age > 12 y/o
          • Use in treatment of acute attacks (not prophylaxis)
          • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as described above
          • For individuals <84 kg, give as 50 units/kg; for individuals > 84 kg give 4,200 units IV.  A second dose can be administered at the same dosage level is acute attack symptoms persist, but no more than 4,200 units should be given in a 24 hour period.
 
Ecallantide (Kalbitor) is a kallikrein inhibitor with a risk of hypersensitivity reactions indicated for treatment of acute attacks of hereditary angioedema (HAE) meeting all of the following criteria:
 
          • Clinical evidence of angioedema with moderate to severe attacks
          • Age > 12 y/o
          • Use in treatment of acute attacks (not prophylaxis)
          • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as  described above
          • Administered SQ as 30 mg (supplied as 10 mg per vial). An additional dose of 30 mg may be administered within a 24 hour period for persistent symptoms.  This drug should be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
  
Icatabant ( Firazyr)  bradykinin B2 receptor antagonist indicated for treatment of acute attacks of hereditary angioedema (HAE) meeting all of the following criteria:
 
          • Clinical evidence of angioedema with moderate to severe attacks
          • Age > 18 y/o
          • Use in treatment of acute attacks (not prophylaxis)
          • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously
          • types 1 HAE and type 2 HAE) as described above
          • Administer as 30 mg injected SQ in the abdominal area (supplied as.  If response is inadequate or symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 hours not to exceed more than 3 injections in 24 hours
 
 Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
The use of a Berinert®, Ruconest, Kalbitor®, or Firazyr® for all other indications does not meet primary coverage criteria. For members with contracts without primary coverage criteria, the use of a Berinert®, Ruconest, Kalbitor®, or Firazyr is investigational and not medically necessary. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The combined use of any of the above drugs for treatment of acute attacks or any other indication does not meet primary coverage criteria. For members with contracts without primary coverage criteria, the combined use any of the above drugs for treatment of acute attacks or any other indication is investigational and not medically necessary. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Long Term HAE Prophylaxis
 
Long term prophylaxis is approved when despite available on-demand acute prophylaxis and/or acute treatment of angioedema attacks, the affected member continues to experience >12 moderate-to severe attacks per year (>1 attacks per month). Given the existence of high-quality trials and long term efficacy, the use of both attenuated androgens and plasma-derived C1 inhibitor meet primary coverage criteria for use in long term prophylaxis:
 
Attenuated androgens (e.g. danazol per FDA approved labeling) meet member benefit certificate primary coverage criteria and are covered when all of the following criteria are met:
 
        • Clinical evidence of angioedema with moderate to severe attacks
        • Has established diagnosis of HAE (as described above)
        • Has >1 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management
        • Is > 16 y/o and/or not a pregnant or breastfeeding
 
 
Plasma derived human C1-INH concentrate (Cinryze or Haegarda) for long term prophylaxis of HAE attacks in adults and adolescents meets member benefit certificate primary coverage criteria and is covered when all of the following criteria are met:
 
Cinryze is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) (C1-INH) indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients with all of the following criteria:
 
        • Has established diagnosis of HAE with C1INH deficiency/ defect (as described above)
        • Has >1 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management
        • Has no contraindication to C1-INH concentrate (e.g. anaphylaxis)
        • Is > 6 years of age
        • Administer as 1,000 units every 3 to 4 days IV*
 
*In rare circumstances with substantial documentation and trials of lower doses, doses up to 2,500 U (not exceeding 100 U/kg) every 3 or 4 days may be considered based on individual patient response.  Doses at this level will require more frequent re-evaluation.  
 
Haegarda is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) (C1-INH) indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients with all of the following criteria:
 
        • Has established diagnosis of HAE with C1INH deficiency/ defect (as described above)
        • Has >1 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management
        • Has no contraindication to C1-INH concentrate (e.g. anaphylaxis)
        • Is > 12 years of age
        • Administer SQ 60 International Units per kg body weight twice weekly (every 3 or 4 days).
 
Authorization should be reviewed at least every six months to confirm that current medical criteria are met and that the medication is effective as defined by at least a 50% decrease in frequency of HAE attacks subsequent to start of therapy, significant improvement/stability in severity and duration of attacks, and clinical documentation of functional improvement/stability.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
Use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) for all indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) is considered investigational for all other indications . Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein inhibitor (i.e., Kalbitor®) does not meet member benefit certificate primary coverage criteria. The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein inhibitor (i.e., Kalbitor®) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective June 2018
 
All drugs administered for continued treatment of HAE with abnormal C1INH deficiency/defect (Type I and Type II HAE) will require  Prior Approval (PA).  None of the below drugs is approved for HAE with Normal C1-INH (previously Type III HAE).
 
Primary coverage criteria are met when a diagnosis of hereditary angioedema is confirmed based on supportive clinical and physical findings combined with results of C4 and C1-INH antigenic and functional activity levels by current or historical testing on two separate occasions with demonstration in both results of either: a) low C4 and C1-INH protein (type 1 HAE) or b) low C4, normal C1-INH, and low functional C1-INH (type 2 HAE).*
 
*Low C4 level--C4 less than 14 mg/dL; normal range 14 to 40 mg/dL, or C4 below the lower limit of normal as defined by the laboratory performing the test.
 
Low C1-INH--(C1-INH) antigenic level (C1INH less than 19 mg/dL; normal range 19 to 37 mg/dL, or C1INH antigenic level below the lower limit of normal as defined by the laboratory performing the test.
 
Low C1-INH functional activity level-- functional C1INH less than 50 % or C1INH functional level below the lower limit of normal as defined by the laboratory performing the test.
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Treatment of  HAE Acute Attacks
 
The below agents meet member benefit certificate primary coverage criteria and are covered for use
in the treatment of acute moderate-severe episodes of established HAE with deficient or dysfunctional C1-INH (craniofacial, laryngeal, or gastrointestinal angioedema). Use is limited to one agent. Combination of below agents for treatment of acute attacks is not allowed.  Prior approval allows members to have sufficient medication for on-demand treatment of two attacks:
 
Plasma derived C1-INH (Berinert ), indicated for the treatment of acute abdominal, facial, or laryngeal hereditary angioedema (HAE) attacks in adult and pediatric patients,  requires all of the following criteria:
 
        • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as described above
        • Clinical evidence of angioedema with moderate to severe attacks
        • Age > 5 y/o
        • Use in treatment of acute attacks (not prophylaxis)
        • 20 units/kg of body weight for the treatment of a HAE acute attack of abdominal, facial, or laryngeal areas in adults or children, administered IV. . A vial contains 500 units.
 
Recombinant C1-INH (Ruconest) indicated for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE)  Effectiveness in the treatment of laryngeal attacks has not been established.  All of the following criteria must be met for the approval of ruconest:
 
        • Clinical evidence of angioedema with moderate to severe attacks, but no history of laryngeal edema
        •  Age > 12 y/o
        • Use in treatment of acute attacks (not prophylaxis)
        • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as described above
        • For individuals <84 kg, give as 50 units/kg; for individuals > 84 kg give 4,200 units IV.  A second dose can be administered at the same dosage level is acute attack symptoms persist, but no more than 4,200 units should be given in a 24 hour period.
 
Ecallantide (Kalbitor) is a kallikrein inhibitor with a risk of hypersensitivity reactions indicated for treatment of acute attacks of hereditary angioedema (HAE) meeting all of the following criteria:
 
        • Clinical evidence of angioedema with moderate to severe attacks
        • Age > 12 y/o
        • Use in treatment of acute attacks (not prophylaxis)
        • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as  described above
        • Administered SQ as 30 mg (supplied as 10 mg per vial). An additional dose of 30 mg may be administered within a 24 hour period for persistent symptoms.  This drug should be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
  
Icatabant ( Firazyr)  bradykinin B2 receptor antagonist indicated for treatment of acute attacks of hereditary angioedema (HAE) meeting all of the following criteria:
 
        • Clinical evidence of angioedema with moderate to severe attacks
        • Age > 18 y/o
        • Use in treatment of acute attacks (not prophylaxis)
        • Established diagnosis of C1-INH deficient or dysfunctional HAE (previously types 1 HAE and type 2 HAE) as described above
        • Administer as 30 mg injected SQ in the abdominal area (supplied as.  If response is inadequate or symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 hours not to exceed more than 3 injections in 24 hours
 
 Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
The use of a Berinert®, Ruconest, Kalbitor®, or Firazyr® for all other indications does not meet primary coverage criteria. For members with contracts without primary coverage criteria, the use of a Berinert®, Ruconest, Kalbitor®, or Firazyr is investigational and not medically necessary. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The combined use of any of the above drugs for treatment of acute attacks or any other indication does not meet primary coverage criteria. For members with contracts without primary coverage criteria, the combined use any of the above drugs for treatment of acute attacks or any other indication is investigational and not medically necessary. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Long Term HAE Prophylaxis
 
Long term prophylaxis is approved when despite available on-demand acute prophylaxis and/or acute treatment of angioedema attacks, the affected member continues to experience >12 moderate-to severe attacks per year (>1 attacks per month). Given the existence of high-quality trials and long term efficacy, the use of both attenuated androgens and plasma-derived C1 inhibitor meet primary coverage criteria for use in long term prophylaxis:
 
Attenuated androgens (e.g. danazol per FDA approved labeling) meet member benefit certificate primary coverage criteria and are covered when all of the following criteria are met:
 
        • Clinical evidence of angioedema with moderate to severe attacks
        • Has established diagnosis of HAE (as described above)
        • Has >1 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management
        • Is > 16 y/o and/or not a pregnant or breastfeeding
 
 
Plasma derived human C1-INH concentrate (Cinryze or Haegarda) for long term prophylaxis of HAE attacks in adults and adolescents meets member benefit certificate primary coverage criteria and is covered when all of the following criteria are met:
 
Cinryze is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) (C1-INH) indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients with all of the following criteria:
 
        • Has established diagnosis of HAE with C1INH deficiency/ defect (as described above)
        • Has >1 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management
        • Has no contraindication to C1-INH concentrate (e.g. anaphylaxis)
        • Is > 6 years of age
        • Administer as 1,000 units every 3 to 4 days IV*
 
*In rare circumstances with substantial documentation and trials of lower doses, doses up to 2,500 U (not exceeding 100 U/kg) every 3 or 4 days may be considered based on individual patient response.  Doses at this level will require more frequent re-evaluation.  
 
Haegarda is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) (C1-INH) indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients with all of the following criteria:
 
            • Has established diagnosis of HAE with C1INH deficiency/ defect (as described above)
            • Has >1 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management
            • Has no contraindication to C1-INH concentrate (e.g. anaphylaxis)
            • Is > 12 years of age
            • Administer SQ 60 International Units per kg body weight twice weekly (every 3 or 4 days).
 
Authorization should be reviewed at least every six months to confirm that current medical criteria are met and that the medication is effective as defined by at least a 50% decrease in frequency of HAE attacks subsequent to start of therapy, significant improvement/stability in severity and duration of attacks, and clinical documentation of functional improvement/stability.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
Use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) for all indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) is considered investigational for all other indications . Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein inhibitor (i.e., Kalbitor®) does not meet member benefit certificate primary coverage criteria. The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein inhibitor (i.e., Kalbitor®) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to June 2018
 
Coverage requires a diagnosis of hereditary angioedema based on supportive clinical and physical findings combined with results of C2, C4 and C1-INH antigenic and functional activity levels by current or historical testing on two separate occasions with demonstration in both results of either: a) low C4 and C1-INH protein (type 1 HAE) or b) low C4, normal C1-INH, and low functional C1-INH (type 2 HAE).*
 
*Low C4 level--C4 less than 14 mg/dL; normal range 14 to 40 mg/dL, or C4 below the lower limit of normal as defined by the laboratory performing the test.
 
Low C1-INH--(C1-INH) antigenic level (C1INH less than 19 mg/dL; normal range 19 to 37 mg/dL, or C1INH antigenic level below the lower limit of normal as defined by the laboratory performing the test.
 
Low C1-INH functional activity level-- functional C1INH less than 50 % or C1INH functional level below the lower limit of normal as defined by the laboratory performing the test.
 
 
Acute Treatment of Attacks
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The below agents meet member benefit certificate primary coverage criteria and are covered for use in the treatment of acute moderate-severe episodes of established HAE (craniofacial, laryngeal, or gastrointestinal angioedema):
 
Berinert (plasma derived C1-INH): 20 units/kg of body weight for the treatment of a HAE acute attack of abdominal, facial, or laryngeal areas in adults or adolescents.  A vial contains 500 units.  
 
Kalbitor (ecallantide): 30 mg (3 vials) for the treatment of acute attacks of HAE in patients 16 years of age and older.  An additional dose of 30 mg may be administered within a 24 hour period for persistent symptoms.  This drug should be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
 
Firazyr (icatabant): 30 mg injected subcutaneously for treatment of acute attacks of HAE in patients 18 years of age and older.  Additional 30 mg doses may be administered at 6 hr intervals to a maximum dose of 3 injections in 24 hours.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) for all other indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, The use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr® is considered investigational for all other indications . Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein inhibitor (i.e., Kalbitor®)does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein inhibitor (i.e., Kalbitor®) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Long Term Prophylaxis
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Long term prophylaxis is approved when despite available on-demand acute prophylaxis and/or acute treatment of angioedema attacks, the affected member continues to experience >12 moderate-to-severe attacks per year (>2 attacks per month). Given the existence of high-quality trials and long term efficacy, the use of both attenuated androgens and plasma-derived C1 inhibitor are covered for use in long term prophylaxis:
 
Attenuated androgens (e.g. danazol per FDA approved labeling) meet member benefit certificate primary coverage criteria and are covered when the member:
        • Has established diagnosis of HAE (as described above)
        • Has >2 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year) despite optimal management  
        •  Is > 16 y/o and/or not  a pregnant or lactating woman
        • Is unable to tolerate attenuated androgens or effective dose exceeds the equivalent of 200mg/day of danazol
        • Has a contraindication to the use of attenuated androgens
        • Has not responded to a documented trial of attenuated androgens (<50% response in attack frequency)
 
Cinryze (plasma derived human C1-INH concentrate) 1,000 units (2 vials) intravenously q 3-4 days for long term prophylaxis of HAE attacks in adults and adolescents meets member benefit certificate primary coverage criteria and is covered when the member:
        • Has established diagnosis of HAE (as described above)
        • Has >2 moderate-to-severe attacks per month (> 12 moderate-to-severe attacks per year)  despite optimal management  
        • Has intolerance, contraindication, or exceeded the recommended dose of attenuated androgens or has not responded to the use of attenuated androgens
        • Has no contraindication to C1-INH concentrate (e.g. anaphylaxis)
 
Authorization shall be reviewed at least every three months to confirm that current medical necessity criteria are met and that the medication is effective as defined by at least a 50% decrease in frequency of HAE attacks subsequent to start of therapy, significant improvement/stability in severity and duration of attacks, and clinical documentation of functional improvement/stability. C1-INH (Cinryze) is considered not medically necessary when used in doses exceeding 1,000 dosage units twice per week (8,000 dosage units every 28 days).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
  
Use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) for all indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of a C1 esterase inhibitor (i.e., Cinryze®, Berinert®), plasma kallikrein inhibitor (i.e., Kalbitor®), or bradykinin B2 receptor antagonist (i.e., Firazyr®) is considered investigational for all other indications . Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein  inhibitor (i.e., Kalbitor®) does not meet member benefit certificate primary coverage criteria. The combined use of a C1 Esterase Inhibitor (i.e., Cinryze®, Berinert®) and a plasma kallikrein  inhibitor (i.e., Kalbitor®) is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Attenuated androgens:
Danazol, an androgen derivative, was evaluated for its effectiveness in preventing attacks of hereditary angioedema in a double-blind study with nine patients. Of 47 placebo courses, 44 ended with attacks, but during 46 danazol courses only one attack occurred. Side effects were minimal, and virilization was not observed in the women studied. C1 esterase inhibitor levels increased three to four times, and levels of the fourth component of complement (C4) increased 15 times. These changes began during the first day of therapy and were maximal by one to two weeks. After therapy was
stopped, C1 esterase inhibitor and C4 levels rapidly decreased. Danazol effectively prevents attacks in hereditary angioedema and acts to correct the underlying biochemical abnormality (2.2% vs 93.6%, P < 0.001, NNT = 3). Evidence of effectiveness for danazol as well as other attenuated androgens has been confirmed on other largely observational studies using lower does to reduce side-effects.
 
Clinical Studies for FDA approval
 
Drugs Approved for Treatment of Acute HAE Attacks
Berinert was evaluated in a prospective, open-label, uncontrolled, multicenter extension study conducted at 15 centers in the US and Canada in subjects who had participated in the RCT study for the treatment of acute abdominal or facial attacks in subjects with HA.
 
The safety analysis of the open-label extension study included a total of 57 subjects, age 10 to 53 years, with 1085 HAE attacks treated with 20 IU/kg body weight dose of Berinert per attack, who were observed at the study siteuntil onset of relief of HAE symptoms, and were followed up for adverse reactions for 7 to 9 days following treatment of each HAE attack During the extension study, 51 subjects experienced 747 abdominal attacks, 21 subjects experienced 51 facial attacks, 30 subjects experienced 235 peripheral attacks, and 16 subjects experienced 48 laryngeal attacks. Some study
subjects may have experienced HAE attacks in more than one location.
 
The prospective open-label extension study demonstrated that, in comparison to untreated historical control data retrospectively collected at a study center in Germany over a 20 year period, the Berinert 20 IU/kg body weight dose appeared to be effective in ameliorating laryngeal HAE attacks by achieving complete resolution of HAE symptoms within 24 hours from attack onset in the majority of subjects. The treatment effects observed with Berinert in the extension study are consistent with the findings from the placebo-controlled efficacy trial.
 
Kalbitor: The safety and efficacy of KALBITOR was evaluated in 2 randomized, double-blind, placebo controlled trials (EDEMA4 and EDEMA3) in 168 patients with HAE. Patients having an attack of hereditary angioedema, at any anatomic location, with at least 1 moderate or severe symptom, were treated with 30 mg subcutaneous KALBITOR or placebo. Because patients could participate in both trials, a total of 143 unique patients participated. Of the 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years. There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks. In both trials, the effects of KALBITOR were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These measures evaluated the severity of attack symptoms at all anatomical locations (MSCS score) and response to therapy (TOS).
 
MSCS score is a point-in-time measure of symptom severity. At baseline, 4 hours, and 24 hours, patients rated the severity on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe) for symptoms at each affected anatomical location. Ratings were averaged to obtain the MSCS score. A decrease in MSCS score reflected an improvement in symptoms.
 
TOS is a measure of symptom response to treatment. At 4 hours and 24 hours, patient assessment of response characterized by their change from baseline in symptom severity and collected by anatomic site of attack involvement, was recorded on a categorical scale (significant improvement [100], improvement [50], same [0], worsening [-50], significant worsening [-100]). The response at each anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS. A TOS value >0 reflected an improvement in symptoms from baseline.
 
EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive KALBITOR 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients with placebo and the results were statistically significant. At 24 hours, patients treated with KALBITOR also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater
TOS (89 vs. 55, p = 0.03).
 
EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive KALBITOR or placebo for acute attacks of HAE. EDEMA3 was similar in design to EDEMA4 with the exception of the order of the prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. As in EDEMA4, patients treated with KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than
patients treated with placebo and the results were statistically significant. In addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR-treated group (5/36, 14%).
 
Firazyr:
Safety and efficacy of this drug for treatment of acute HAE attacks in adults were studied in three trials with 223 participants with an average age of 38 years. Many of these patients reported use of attenuated androgens, antifibrinolytic agents or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptoms for abdominal and cutaneous pain and swelling.
 
Long-term studies to determine the carcinogenic potential of icatibant have not been conducted.
 
There are a number of ongoing trials for all the drugs, several in the European countries, with enrollments of 12 to 149 subjects. There are no trials for Type III HAE.
 
Ruconest
The safety and efficacy of RUCONEST for treatment of acute angioedema attacks in patients with HAE was established in Study 1, a double-blind randomized, placebo-controlled trial (RCT) which included an open-label extension phase (OLE); and supported by the results of 2 additional RCTs and 2 additional OLE studies.  
 
The safety and efficacy of RUCONEST in the treatment of acute attacks in patients with hereditary angioedema were demonstrated in a placebo-controlled, double-blind, randomized study (Study 1).  Supportive evidence of effectiveness is provided by two double-blind, randomized, placebo-controlled studies (Studies 2 and 3).  Evidence for the efficacy of repeat treatment of HAE attacks is provided from the OLE of each of the three randomized studies.  
 
In September 2017 a study with pooled data from three RCTs,(NCT00225147 [C1-1205), NCT00262301 [C1-1304], and NCT01188564 [C1-1301]) with OLEs examined rhC1-INH for treatment of acute HAE attacks with upper airway involvement was published (Riedl M, Li H, Cicardi M, et al, 2017).  Patients with functional plasma C1 esterase inhibitor <50% of normal who had experienced an acute upper airway HAE attach and received rhC1-INH were identified retrospectively based on severity of breathing or swallowing symptoms.  The primary end point was the time to beginning of reflief (time at which the overall visual analog scale score [0-100 mm] decreased from baseline by >20mm for two consecutive time points [persistence]) (Riedl M, Li H, Cicardi M, et al, 2017) .  
 
Of 683 acute HAE attacks treated with rhC1-INH, data for 45 attacks with upper airway involvement were included.  The median time to the beginning of symptom relief was 67 minutes 995% confidence interval, 60-120 minutes) and did not differ by attack number or by baseline breathing or swallowing symptom severity.  Most attacks (91.1%) achieved the beginning relief within 4 hrs of rhC1-INH treatment.  All attacks resolved without the need for any additional medication, and no patients required intubation or tracheostomy.  Treatment with rhC1-INH was well tolerated, with no adverse events reported in more than one patient (except HAE reported as an adverse event [n=2]) (Riedl M, Li H, Cicardi M, et al, 2017) .
 
Drugs Approved for Long-term  HAE Prophylaxis
Cinryze: The safety and efficacy of CINRYZE prophylaxis therapy to reduce the incidence, severity, and duration of HAE attacks was demonstrated in a single randomized, double blind, placebo controlled multi-center cross-over study of 24 patients. Patients were screened to confirm a diagnosis of HAE and a history of at least two HAE attacks per month. 24 patients (mean age 38.1 years with a range of 9 to 73 years) were randomized to one of two treatment groups: either CINRYZE prophylaxis for 12 weeks followed by 12 weeks of placebo prophylaxis; or randomized to placebo prophylaxis for 12 weeks followed by 12 weeks of CINRYZE prophylaxis. Two subjects dropped out (one in each
arm); 22 patient crossed over into period 2 and were included in the efficacy analysis. Patients were given blinded injections (CINRYZE or placebo) every 3 to 4 days, approximately 2 times per week. Patients recorded all angioedema symptoms daily. An attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day.
 
The efficacy determination was based on the number of attacks during the 12-week period while receiving CINRYZE as compared to the number of attacks during the placebo treatment period. The effectiveness of C1 esterase inhibitor prophylaxis in reducing the number of HAE attacks was variable among the subjects.
 
The critical COMPACT trial of Haegarda has already been described in detail.  Results of a phase II trial have also been published.  This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 subjects with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated, volume-reduced Haegarda for 4 weeks each.  The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated.  The primary outcome was model-derived steady-state trough C1-INH functional activity.  After SC administration of Haegarda, a dose-dependent increase in trough functional C1-INH activity was observed.  C1-INH and C4 levels both increased.  The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, which was a threshold that was assumed to provide clinical protection against attacks.  Compared with intravenous injection, C1-INH SC injections of Haegarda showed a lower peak-to-trough ratio and more consistent exposures.  All doses were well tolerated.  Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event.  The authors concluded that SC volume-reduced Haegarda was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels.  However, the authors of this trial noted that a clinical outcome study of SC Haegarda in HAE warrants further investigation (Zuraw, 2015).

CPT/HCPCS:
C9015Injection, c-1 esterase inhibitor (human), haegarda, 10 units
J0596Injection, c1 esterase inhibitor (recombinant), ruconest, 10 units
J0597Injection, C-1 esterase inhibitor (human), Berinert, 10 units
J0598Injection, C-1 esterase inhibitor (human), Cinryze, 10 units
J0599Injection, c-1 esterase inhibitor (human), (haegarda), 10 units
J1290Injection, ecallantide, 1 mg
J1744Injection, icatibant, 1 mg

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