Pediatric Angioedema Medication
- Author: Shih-Wen Huang, MD; Chief Editor: Harumi Jyonouchi, MD more...
Treatment of urticaria-related angioedema is the same as that for urticaria. Drug therapy for hereditary angioedema (HAE) may be preventive or for the treatment of an acute attack. Few pediatric cases have been reported. Minor episodes of subepithelial swelling need no treatment, but patients with edema of the face and neck should be closely observed for spreading and for signs of airway involvement. Airway involvement can be a true medical emergency in this disorder.
Oral androgens have provided the most successful preventive therapy. Synthetic attenuated androgens (eg, danazol, oxandrolone) taken prophylactically increase the serum concentration of C1 inhibitor (C1INH), presumably by enhancing the function of the C1INH gene (SERPING1). When danazol is used prophylactically in adolescents or preadolescents, the concentration of C1INH and C4 are increased in the plasma.
This agent increases levels of C4 component of complement and reduces attacks associated with angioedema. In HAE, danazol increases level of deficient C1 esterase inhibitor.
Oxymetholone is an anabolic and androgenic derivative of testosterone formulated for oral administration. It is a synthetic attenuated androgen with relatively few adverse effects.
Oxandrolone is considered one of the safer anabolic steroids available. It has gained orphan drug status to treat Turner syndrome, constitutional delayed growth or puberty of boys, and alcoholic hepatitis, and has recently been used to treat AIDS-wasting syndrome. Hepatotoxicity (more commonly observed in the group receiving 17 alpha alkylated androgen) has not been observed. Oxandrolone may prevent HAE in cases where other androgens were ineffective.
These agents have been successfully used as preventive therapy. The effect may depend on physiologic or pathologic enhancement of plasminogen activation in blood, which may promote activation of C1INH.
Aminocaproic acid is an antifibrinolytic agent used for immediate short-term treatment of angioedema. It inhibits fibrinolysis via the inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It is widely distributed. The half-life is 1-2 hours. For the inhibition of angioedema, several days of treatment may be required. Hepatic metabolism is minimal. This agent can be used orally or intravenously.
It is thought to prevent extensive edema formation after the onset of an attack. Even if the patient has bouts of intestinal edema, symptoms are markedly ameliorated.
Tranexamic acid is used for immediate short-term treatment. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also prevents extensive edema formation and helps ameliorate intestinal symptoms.
Fresh frozen plasma (FFP) is used for treatment of acute attacks. Replacement therapy is logical in the case of an ongoing attack. Numerous reports indicate that FFP may relieve an episode of edema; on the other hand, symptoms may worsen because FFP also contains sufficient substrate to the enzyme that is to be replaced.
The differences in response to this treatment probably result from differences between the onset of symptoms and the time of an attack. When patient arrives at the emergency department (ED), the attack has probably been underway for a number of hours or more than a day. Some believe that early administration of FFP may worsen edema.
Plasma is the fluid compartment of blood containing many components essential to the complement cascade (ie, C1 esterase inhibitor).
These agents directly or indirectly stimulate adrenergic receptors. They are used as supportive emergency treatment for airway edema.
An oropharyngeal spray of 1:1000 racemic epinephrine helps reduce edema, especially in the upper airway (eg, laryngeal edema).
This agent elicits specific kallikrein inhibitor activity resulting in bradykinin reduction. It is useful for treating acute episodic attacks. The package insert carries a black box warning because a small subset of patients may have anaphylactic reactions to the drug. It must be administered by medical personnel capable of treating anaphylaxis.
A human plasma kallikrein inhibitor, ecallantide binds to plasma kallikrein and blocks its binding site. It reduces conversion of kininogen to bradykinin. Ecallantide is indicated for acute attacks of HAE in adults and children aged 12 years or older. It is available as injectable solution, at 10 mg/mL per single-use vial.
Bradykinin Receptor Antagonists
Bradykinin receptor antagonists such as icatibant inhibit bradykinin from binding the B2 receptor and thereby treat the clinical symptoms of an acute attack. Recommended dose of icatibant is 30 mg SC in the abdominal area. It is available as a single-use, prefilled syringe, which delivers a dose of 30 mg (10 mg/mL). Safety and efficacy has not been established in patients younger than 18 years.
Icatibant is a bradykinin B2 receptor antagonist indicated for acute attacks of HAE.
Serine Proteinase Inhibitors (serpins)
These agents recently received approval from the US Food and Drug Administration (FDA) for use in HAE. They are derived from human plasma.
C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). It regulates activation of pathway for complement and intrinsic coagulation, as well as the fibrinolytic system. It binds to and neutralizes substrates that activate these systems, thereby suppressing activity.
This agent is available as a sterile, lyophilized preparation derived from human plasma. Specific activity is 4-9 U/mg protein. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. It is indicated for routine prophylaxis against angioedema attacks in adolescents and adults with HAE.
C1-INH some of the missing protein, but its half-life in the circulation is short. Approved use is 1000 units biweekly, with the possibility of a third dose of 1000 units/wk if needed. Although FDA approval is for prophylaxis only at this time, this agent has been available for treatment of acute attacks in Europe for decades and has an excellent safety profile.
Recombinant C1 esterase inhibitor is from the milk of genetically modified (transgenic) rabbits. It restores the level of functional C1-esterase inhibitor in a patient's plasma, thereby treating the acute attack of swelling. It is indicated for adolescents and adults to treat acute attacks of HAE. Efficacy for treatment of laryngeal attack was not established.
Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004 Sep. 114(3 Suppl):S51-131. [Medline].
Patel NN, Patel DN. Hereditary angioedema with normal C1 inhibitor. Am J Med. 2008 Nov. 121(11):949-51. [Medline].
Visy B, Fust G, Varga L, et al. Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol (Oxf). 2004 Apr. 60(4):508-15. [Medline].
Cichon S, Martin L, Hennies HC, Muller F, Van Driessche K, Karpushova A. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 2006 Dec. 79(6):1098-104. [Medline].
Prieto A, Tornero P, Rubio M, Fernandez-Cruz E, Rodriguez-Sainz C. Missense mutation Thr309Lys in the coagulation factor XII gene in a Spanish family with hereditary angioedema type III. Allergy. 2009 Feb. 64(2):284-6. [Medline].
Duan QL, Binkley K, Rouleau GA. Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. J Allergy Clin Immunol. 2009 Jan 27. [Medline].
[Guideline] Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):24. [Medline]. [Full Text].
Kumar A, Khamkar K, Gopal H. Serum sickness and severe angioedema following rituximab therapy in RA. Int J Rheum Dis. 2012 Feb. 15(1):e6-7. [Medline].
Toklu Y, Sarac O, Berk S, Simsek S. Angioedema after intravitreal bevacizumab injection. Cutan Ocul Toxicol. 2012 Mar. 31(1):85-6. [Medline].
Tukenmez Demirci G, Kivanc Altunay I, Atis G, Kucukunal A. Allergic contact dermatitis mimicking angioedema due to paraphenylendiamine hypersensitivity: a case report. Cutan Ocul Toxicol. 2012 Sep. 31(3):250-2. [Medline].
Studdiford JS, Conniff KM, Trayes KP, Tully AS. Bedbug infestation. Am Fam Physician. 2012 Oct 1. 86(7):653-8. [Medline].
Miller DG, Sweis RT, Toerne TS. Penile angioedema developing after 3 years of ACEI therapy. J Emerg Med. 2012 Aug. 43(2):273-5. [Medline].
Huang SW. Results of an on-line survey of patients with hereditary angioedema. Allergy Asthma Proc. 2004 Mar-Apr. 25(2):127-31. [Medline].
Perricone C, Agmon-Levin N, Shoenfeld N, de Carolis C, Guarino MD, Gigliucci G, et al. Evidence of impaired sense of smell in hereditary angioedema. Allergy. 2010 Jul 22. [Medline].
Nakachi S, Inokuma S. Eleven cases of angioedema with eosinophilia treated in a single hospital in Japan. Allergol Int. 2012 Jun. 61(2):259-63. [Medline].
Cugno M, Zanichelli A, Bellatorre AG, Griffini S, Cicardi M. Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency. Allergy. 2009 Feb. 64(2):254-7. [Medline].
Kusuma A, Relan A, Knulst AC, et al. Clinical impact of peripheral attacks in hereditary angioedema patients. Am J Med. 2012 Sep. 125(9):937.e17-24. [Medline].
Sánchez-Borges M, Asero R, Ansotegui IJ, et al. Diagnosis and Treatment of Urticaria and Angioedema: A Worldwide Perspective. World Allergy Organ J. 2012 Nov. 5(11):125-147. [Medline].
Jaiganesh T, Hughan C, Webster A, Bethune C. Hereditary angioedema: a survey of UK emergency departments and recommendations for management. Eur J Emerg Med. 2012 Aug. 19(4):271-4. [Medline].
Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008. 68(18):2561-73. [Medline].
Reshef A, Leibovich I, Goren A. Hereditary angioedema: new hopes for an orphan disease. Isr Med Assoc J. 2008 Dec. 10(12):850-5. [Medline].
Bernstein JA, Ritchie B, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz DS, et al. Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2010 Aug. 105(2):149-54. [Medline].
Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014 Feb. 112(2):163-169.e1. [Medline].
Cicardi M et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. Aug 2010. 363:523-31.
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):532-41. [Medline]. [Full Text].
Lumry WR, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. American Academy of Allergy, Asthma, & Immunology Meeting. March 22, 2011; Abstract L2.
Zuraw BL et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. Aug 2010. 363:513-22.
Birjmohun RS, Kees Hovingh G, Stroes ES, et al. Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema. Clin Ther. 2008 Dec. 30(12):2314-23. [Medline].
Zanichelli A, Badini M, Nataloni I, Montano N, Cicardi M. Treatment of acquired angioedema with icatibant: a case report. Intern Emerg Med. 2010 Aug 3. [Medline].
Herrmann G, Schneider L, Krieg T. Efficacy of danazol treatment in a patient with the new variant of hereditary angio-oedema (HAE III). Br J Dermatol. 2004 Jan. 150(1):157-8. [Medline].
[Guideline] Grattan CE, Humphreys F. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol. 2007 Dec. 157(6):1116-23. [Medline].
Morgan BP. Hereditary angioedema--therapies old and new. N Engl J Med. 2010 Aug 5. 363(6):581-3. [Medline].