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MP 5.01.108 Pharmacologic Treatment of Hereditary Angioedema

Medical Policy    
Prescription Drug 
Original Policy Date
Last Review Status/Date
Local policy created with literature search/7:2010 
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.



1. Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant genetic disease in which there is inadequate or nonfunctional complement-1 esterase inhibitor (C1-INH) in the blood.

HAE is characterized by episodic, sudden, acute attacks of intense localized edema causing swelling. The swelling can occur almost anywhere but is commonly found in the following body parts: extremities, intestines (abdomen), face, larynx, genitals.

Swelling attacks can occur unpredictably and vary in severity and frequency.

2. HAE is diagnosed by clinical history, diagnostic tests and exclusion of other causes of angioedema. The specific tests required to make the diagnosis include C4, C1q, and C1-INH (antigenic or functional level). Genetic testing is not necessary to confirm the diagnosis of HAE.

3. Medications used for long-term prevention of HAE attacks include:

  • Attenuated Androgens
    • danazol (Danocrine®)
    • stanozolol (Winstrol®)
    • oxandrolone (Oxandrin®)
  • Antifibrinolytics
    • Epsilon-aminocaproic acid (Amicar®)
    • Tranexamic acid (Lysteda™)

Of these only danazol has FDA approval for this indication.

4. Medications used for short-term prevention of HAE attacks include:

  • Attenuated Androgens
    • danazol (Danocrine®)
    • stanozolol (Winstrol®)
  • Antifibrinolytics
    • Tranexamic acid (Lysteda™)

5. Medications used for treatment of acute HAE attacks include:

  • Attenuated Androgens
    • danazol (Danocrine®)
    • stanozolol (Winstrol®)
  • Antifibrinolytics
    • Tranexamic acid (Lysteda™)
  • Other
    • Fresh frozen plasma

None of which have FDA approval for this indication



C1 esterase-inhibitor (Cinryze™) may be considered medically necessary for routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE). C1 esterase-inhibitor (Berinert®) may be considered Medically Necessary for the treatment of acute abdominal or facial attacks of HAE in adult and adolescent patients.  Ecallantide (Kalbitor®) may be considered Medically Necessary for the treatment of acute attacks of HAE in patients 16 years of age and older.

For long-term prophylaxis 1-inhbitor may be considered medically necessary as second line therapy only upon failure of treatment with attenuated androgens such as danazol and/or antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid.

C1-inhibitor therapy is considered investigational for the treatment of:

  • sepsis and endotoxic shock
  • capillary leak syndrome
  • pancreatitis
  • Pneumococcal meningitis
  • malaria
  • xenotranplantation
  • ischemia-reperfusion injury
  • antiotensin-converting enzyme inhibitor induced angioedema.

The use of ecallantide is considered investigational for its use in cardiopulmonary bypass surgery to reduce post-operative blood loss.

Policy Guidelines

Treatment of acute HAE attacks

Consensus-based guidelines from the U.K.4 and Canada5 recommend that the treatment of acute attacks depends on severity:

  • Attacks involving only peripheral swelling usually do not require treatment.
  • ome patients receiving danazol (Danocrine®) prophylaxis can abort attacks by increasing the dose of danazol (Danocrine®) at the first signs or prodrome of an attack.
  • If there is any suspicion of airway involvement, Berinert® should be given promptly.*
  • For acute attacks of abdominal edema, pain relief should be given at an appropriate level, including nonsteroidal anti-inflammatory drugs and opiates. If the attack is severe, Berinert® or fresh frozen plasma (FFP) may be given.* FFP may worsen symptoms during an acute attack because it contains high concentrations of complement components.

*Note, these guidelines were published before the development of ecallantide (Kalbitor®).

The selection of Berinert® or Kalbitor® for the treatment of acute HAE attacks may be guided by the following considerations:

  • Route of administration (intravenous Berinert® vs. subcutaneous ecallantide [Kalbitor®])
  • Increased risk of anaphylaxis associated with ecallantide (Kalbitor®)
  • Treatment of acute HAE attacks with C1-INH (Berinert®) in patients who are receiving prophylaxis of HAE attacks with C1-INH (Cinryze™) may increase the risk of thromboembolism due to elevated levels of C1-INH; studies examining the use of Berinert® or ecallantide (Kalbitor®) for the treatment of acute HAE attacks in patients receiving long-term prophylaxis with Cinryze™ have not been reported.

Prophylaxis of acute HAE attacks


For minor procedures, e.g., dental work, endoscopy, childbirth:

a. If Cl-inhibitor will be immediately available, then no prophylaxis is required.

b. If Cl-inhibitor will not be immediately available, danazol (Danocrine®) for 5 days before and 2 days after the procedure, or tranexamic acid (LystedaTM) for 48 hours before and after the procedure, may be given.

For major procedures, i.e., requiring intubation:

a. C1-inhibitor therapy is recommended one hour prior to surgery.
b. If C1-inhibitor is not available, danazol (Danocrine®) or fresh frozen plasma one or more hours prior to surgery is recommended.


The guidelines recommend that the decision to use long-term prophylaxis in any affected individual should be guided by the severity of the disease. Frequent attacks of peripheral angioedema, although unpleasant and annoying, are not dangerous and may not require long-term prophylaxis.



FDA. STN125267. CINRYZE™ (C1 Inhibitor) for routine prophylaxis against HAE attacks. Lev Pharmaceuticals, Inc. Final Clinical Review. Available online at: Last viewed May 2010.

Craig TJ, Levy RJ, Wasserman RL et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol  2009; 124:801-8.


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Gompels MM, Lock RJ, Abinun M et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005; 139(3):379-94.

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Levi M, Choi G, Picavet C et al. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006;114(4):904-8.

Caliezi C, Zeerleder S, Redondo M et al. C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction. Crit Care Med 2002; 30:1722-1728.

Tassani P, Kunkel R, Richter JA et al. Effect of C1-esterase-inhibitor on capillary leak and inflammatory response syndrome during arterial switch operations in neonates. J  ardiothorac Vasc Anesth 2001; 15(4):469-73.

Fattouch K, Bianco G, Speziale G et al. Beneficial effects of C1-esterase inhibitor in STelevation myocardial infarction in patients who underwent surgical reperfusion: a  randomized double-blind study. Eur J Cardithorac Surg 2007; 32:326-32.

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Frank MM, Jiang H. New therapies for hereditary angioedema: disease outlook changes dramatically. J Allergy Clin Immunol 2008; 121(1):272-80.

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Frank MM, Sergent JS, Kane MA et al. Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study. N Engl J Med 1972; 286:808-12.

Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: safety of long-term stanozolol Therapy. J Allergy Clin Immunol 2007; 120:654-8.

Jaffe CJ, Atkinson JP, Gelfand JA et al. Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery. J Allergy Clin Immunol 1975;55:386-93.

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Bauernschmitt R, Böhrer H, Hagl S. Rescue therapy with C1-esterase inhibitor concentrate after emergency coronary surgery for failed PTCA. Intensive Care Med 1998; 24(6):635-8.

Buerke M, Prüfer D, Dahm M et al. Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury. J Pharmacol Exp Ther 1998; 286(1):429-38.

Schneider DT, Nürnberger W, Stannigel H et al. Adjuvant treatment of severe acute pancreatitis with C1 esterase inhibitor concentrate after haematopoietic stem cell transplantation. Gut 1999;45(5):733-6.

Strüber M, Hagl C, Hirt SW et al. C1-esterase inhibitor in graft failure after lung transplantation. Intensive Care Med 1999; 25(11):1315-8.

Marx G, Nashan B, Cobas Meyer M et al. Septic shock after liver transplantation for Caroli’s disease: clinical improvement after treatment with C1-esterase inhibitor. Intensive Care Med 1999;25(9):1017-20.

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Nürnberger W, Heying R, Burdach S et al. C1 esterase inhibitor concentrate for capillary leakage syndrome following bone marrow transplantation. Ann Hematol 1997; 75(3):95-101.

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HCPCS  J0598 Injection, C1 esterase inhibitor (human), 10 units 
  C9263 Injection, ecallantide, 1 mg 
ICD-10-CM (effective 10/1/15) R65 sepsis code range
  K85, K86 pancreatitis code range
  B53-B53.0;B54 malaria code range
  V42.89 unspecified organ or tissue transplant
  T46.4X5S, T46.4X5A adverse effect of angiotensin-converting-enzyme inhibitor

Policy History

Date Action Reason
07/16/10 Add to Prescription Drug section New policy (local)


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