Charleston, SC


Hereditary Angioedema (HAE)


  1. HAE results from a deficiency in quantity or function of C1 inhibitor (C1-INH) due to a genetic defect
    1. A rare, autosomal-dominant disorder that manifests in early childhood 
  2. Swelling in HAE results from excess bradykinin production, which is a potent vasodilatory mediator 
    1. Histamine and other mast cell mediators are not directly involved 
  3. HAE attacks are classified as laryngeal, cutaneous, or gastrointestinal 
    1. Laryngeal attacks are the least common but most serious due to possible airway obstruction
  4. Treatment involves airway management, empiric treatment, and targeted treatments
    1. Empiric treatment with antihistamines (e.x. IV diphenhydramine and famotidine), corticosteroids (IV methylprednisolone, dexamethasone)

i. While antihistamines are generally ineffective it is recommended to still do a trial of these medications

  • IM epinephrine recommended for anaphylaxis, severe laryngeal edema, or respiratory distress
    • Targeted treatment by C1-INH replacement, Bradykinin B2 receptor blocker, plasma kallikrein inhibitor
Medication C1-INH Concentrates (Berinert, Cinryze)  Conestat alfa (Ruconest)Icatibant (Firazyr)Ecallantide (Kalbitor)Fresh Frozen Plasma (FFP)
Dose20 units/kg over 10 min50 units/kg over 5 min (max 4,200 units)30 mg slow (may repeat every 6 hours (max 90 mg/day)30 mg (may repeat one time within 24 hours)2 units 
AdministrationIVIVSubcutaneous SubcutaneouslyIV 
MechanismCI-INH replacement CI-INH replacementBradykinin B2 receptor antagonistPlasma kallikrein inhibitor CI-INH replacement 
Onset 30-60 minutes90 minutes120 minutes 30 minutes to 4 hrs2 to 4 hours
Adverse EffectsHeadache, skin rash, injection site reactions, thrombotic eventsHeadache, injection site reactions, thrombotic eventsInjection site reactions, increased transaminases, feverHeadache, fatigue, nausea, diarrhea, skin rashVolume overload 
Drug Interactions Androgens, estrogens, and progestins may enhance effect Androgens, estrogens, and progestins may enhance effectMay reduce the antihypertensive effect of ACEinhibitors No significant interactions Transfusion-related reactions, thrombotic events, hypocalcemia
CommentsMust be warmed to room temp Preferred therapy for children and in pregnancy Must be warmed to room temp  Maximum of 4200 units in 24 hrs Indicated in patients > 18 years of age Caution in ischemic heart disease BBW: Anaphylaxis (must be administered by a medical professional)Monitor for volume  2nd line to other C1-INH therapies 
Price Tag $~ $3,500 per 500 units ~ $7,100 per 2,100 units ~ $2,000-4,000 per 10 mg~ $6,000 per 10 mg ~ $ 55 per unit

Jlpruitt@gmh.edu                                                                                                                                                            For educational purposes only

 Overview of Evidence 
Author, year Design/ sample sizeIntervention & ComparisonOutcome
2017 Li Randomized, double-blind, placebo- controlled  (n=43)IV recombinant human C1-INH (rhC1-INH) 50 units/kg (max of 4,200 units) or placebo to patients with a severe HAE attack RhC1-INH significantly reduced the time to onset symptom relief (90 min vs 334 min) and also required less rescue therapy  
2017 FarkasMulticenter, openlabel, nonrandomized  (n=32)Pediatric patients (< 18 years old) received subcutaneous icatibant (0.4 mg/kg, max 30 mg)Icatibant was well tolerated, injection-site reactions with erythema and swelling were most common (90.6% of patients)
2014 RiedlRandomized, placebocontrolled (n=75) IV rhC1-INH 50 units/kg (max of 4,200 units) or placebo  RhC1-INH significantly reduced the time to onset symptom relief (90 min vs 152 min) with no differences in adverse events 
2011 LumryRandomized, double-blind, placebocontrolled (n=93)Subcutaneous icatibant 30 mg or placeboIcatibant significantly reduced median times in symptom severity reduction, the onset of symptom relief, complete symptom relief  No difference in the incidence of adverse events 
2010 CicardiTwo randomized, double-blind trials  (n=56, n= 74)Subcutaneous icatibant 30 or placebo Subcutaneous icatibant 30 mg or PO tranexamic acid 3 gm Icatibant significantly reduced time to complete symptom resolution compared to placebo and tranexamic acid 
2010LevyRandomized, double-blind, placebocontrolled (n=96)Subcutaneous ecallantide 30 mg or placebo  Ecallantide significantly mean symptom complex severity score at 4 hours and treatment outcome score throughout 24 hours
2010 CicardiRandomized, double-blind, placebocontrolled (n=72)Subcutaneous ecallantide 30 mg or placebo  Improvement in patient-reported treatment scores No difference in time to significant improvement or adverse effects 


  • There is a lack of response to antihistamines and corticosteroids in HAE due to the underlying pathophysiology of the disease  o      While there is no proven benefit it is still recommended to give these agents in case there is an underlying allergic reaction occurring
  • FFP is inexpensive but not routinely used in clinical practice for HAE
  • Berinert is the preferred therapy in children < 12 year of age and pregnancy 
  • Recombinant human C1-INH, Icatibant and Ecallantide have provided evidence of safety and efficacy in HAE 


  1. Craig TJ, et al. J Allergy Clin Immunol 2009;124:801-8.
  2. Zuraw BL, et al. N Engl J Med 2010; 363:513-22.
  3. Li HH, et al. Allergy Asthma Proc 2017;38(6):456.
  4. Farlkas H, et al. J Allergy Clin Immunol Pract. 2017;5(6):1671.
  5. Riedl MA, et al. Ann Allergy Asthma Immunol. 2014;112(2):163-169.
  6. Lumry WR, et al. Ann Allergy Asthma Immunol. 2011;107:529-37. 
  7. Cicardi M, et al. N Engl J Med. 2010;363:532-41.
  8. Prematta M, et al. Ann Allergy Asthma. 2007; 98:383-8.
  9. Levy RJ, et al. Ann Allergy Asthma Immunol. 2010; 104:523-9.


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