Introduction

HAE results from a deficiency in quantity or function of C1 inhibitor (C1-INH) due to a genetic defect

A rare, autosomal-dominant disorder that manifests in early childhood

Swelling in HAE results from excess bradykinin production, which is a potent vasodilatory mediator

Histamine and other mast cell mediators are not directly involved

HAE attacks are classified as laryngeal, cutaneous, or gastrointestinal

Laryngeal attacks are the least common but most serious due to possible airway obstruction

Clinical Detail

Empiric treatment with antihistamines (e.x. IV diphenhydramine and famotidine), corticosteroids (IV methylprednisolone, dexamethasone)

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

Evidence

Evidence details are preserved from the source document in the clinical sections and references.

Conclusions

There is a lack of response to antihistamines and corticosteroids in HAE due to the underlying pathophysiology of the disease

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

References

  • Craig TJ, et al. J Allergy Clin Immunol 2009;124:801-8.
  • Zuraw BL, et al. N Engl J Med 2010; 363:513-22.
  • Li HH, et al. Allergy Asthma Proc 2017;38(6):456.
  • Farlkas H, et al. J Allergy Clin Immunol Pract. 2017;5(6):1671.
  • Riedl MA, et al. Ann Allergy Asthma Immunol. 2014;112(2):163-169.
  • Lumry WR, et al. Ann Allergy Asthma Immunol. 2011;107:529-37.
  • Cicardi M, et al. N Engl J Med. 2010;363:532-41.
  • Prematta M, et al. Ann Allergy Asthma. 2007; 98:383-8.
  • Levy RJ, et al. Ann Allergy Asthma Immunol. 2010; 104:523-9.
    •  C1-INH Concentrates
    (Berinert, Cinryze)    		Conestat alfa (Ruconest)Icatibant (Firazyr)Ecallantide (Kalbitor)Fresh Frozen Plasma (FFP)
    Dose20 units/kg over 10 min (Berinert)50 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
    AdministrationIVIVSubcutaneousSubcutaneouslyIV
    MechanismCI-INH replacementCI-INH replacementBradykinin B2 receptor antagonistPlasma kallikrein inhibitorCI-INH replacement
    Onset30-60 minutes90 minutes120 minutes30 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 InteractionsAndrogens, estrogens, and progestins may enhance effectAndrogens, estrogens, and progestins may enhance effectMay reduce the antihypertensive effect of ACE-inhibitorsNo significant interactionsTransfusion-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
    Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
    2017 LiRandomized, 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 attackRhC1-INH significantly reduced the time to onset symptom relief (90 min vs 334 min) and also required less rescue therapy
    2017 FarkasMulticenter, open-label, 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, placebo-controlled (n=75)IV rhC1-INH 50 units/kg (max of 4,200 units) or placeboRhC1-INH significantly reduced the time to onset symptom relief (90 min vs 152 min) with no differences in adverse events
    2011 LumryRandomized, double-blind, placebo-controlled (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
    2010 LevyRandomized, double-blind, placebo-controlled (n=96)Subcutaneous ecallantide 30 mg or placeboEcallantide significantly mean symptom complex severity score at 4 hours and treatment outcome score throughout 24 hours
    2010 CicardiRandomized, double-blind, placebo-controlled (n=72)Subcutaneous ecallantide 30 mg or placeboImprovement in patient-reported treatment scores
    No difference in time to significant improvement or adverse effects
    Tags: HAE C1 inhibitor bradykinin angioedema

    Source Artifact

    Copy of Angioedema_Pharmacy Friday.Wa1. jlp2.docx (local DOCX source artifact; public source link pending)