Hereditary Angioedema

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

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

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

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.

Pharmacology | Pharmacology | Pharmacology | Pharmacology | Pharmacology | Pharmacology

Medication | C1-INH Concentrates (Berinert, Cinryze) | Conestat alfa (Ruconest) | Icatibant (Firazyr) | Ecallantide (Kalbitor) | Fresh Frozen Plasma (FFP)

Dose | 20 units/kg over 10 min | 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

Administration | IV | IV | Subcutaneous | Subcutaneously | IV

Mechanism | CI-INH replacement | CI-INH replacement | Bradykinin B2 receptor antagonist | Plasma kallikrein inhibitor | CI-INH replacement

Onset | 30-60 minutes | 90 minutes | 120 minutes | 30 minutes to 4 hrs | 2 to 4 hours

Adverse Effects | Headache, skin rash, injection site reactions, thrombotic events | Headache, injection site reactions, thrombotic events | Injection site reactions, increased transaminases, fever | Headache, fatigue, nausea, diarrhea, skin rash | Volume overload

Drug Interactions | Androgens, estrogens, and progestins may enhance effect | Androgens, estrogens, and progestins may enhance effect | May reduce the antihypertensive effect of ACE-inhibitors | No significant interactions | Transfusion-related reactions, thrombotic events, hypocalcemia

Comments | Must 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

Overview of Evidence | Overview of Evidence | Overview of Evidence

Author, year | Design/ sample size | Intervention & Comparison | Outcome | Outcome

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 | RhC1-INH significantly reduced the time to onset symptom relief (90 min vs 334 min) and also required less rescue therapy

2017 Farkas | Multicenter, 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) | Icatibant was well tolerated, injection-site reactions with erythema and swelling were most common (90.6% of patients)

2014 Riedl | Randomized, placebo-controlled (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 | RhC1-INH significantly reduced the time to onset symptom relief (90 min vs 152 min) with no differences in adverse events

2011 Lumry | Randomized, double-blind, placebo-controlled (n=93) | Subcutaneous icatibant 30 mg or placebo | Icatibant significantly reduced median times in symptom severity reduction, the onset of symptom relief, complete symptom relief No difference in the incidence of adverse events | Icatibant 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 Cicardi | Two 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 | Icatibant significantly reduced time to complete symptom resolution compared to placebo and tranexamic acid

2010 Levy | Randomized, double-blind, placebo-controlled (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 | Ecallantide significantly mean symptom complex severity score at 4 hours and treatment outcome score throughout 24 hours

2010 Cicardi | Randomized, double-blind, placebo-controlled (n=72) | Subcutaneous ecallantide 30 mg or placebo | Improvement in patient-reported treatment scores No difference in time to significant improvement or adverse effects | Improvement in patient-reported treatment scores No difference in time to significant improvement or adverse effects