Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Hereditary Angioedema Medication

  • Author: Michael M Frank, MD; Chief Editor: Michael A Kaliner, MD  more...
 
Updated: Feb 25, 2015
 

Medication Summary

The goals of pharmacotherapy for hereditary angioedema (HAE) are to reduce morbidity and to prevent complications. Medication may be used for acute or preventive treatment.

In Europe, purified C1 inhibitor (C1-INH) has been available for treatment of acute attacks for decades, but it has not been available in the United States until recently.[13, 38, 39] In October 2008, the US Food and Drug Administration (FDA) approved the use of C1-INH (Cinryze) at a dose of 1000 units IV 2-3 times/week for prophylaxis to prevent attacks. In October 2009, the FDA approved C1-INH (Berinert) at a dose of 20 units/kg IV for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE.[7] In January 2012, an additional indication for laryngeal angioedema was approved by the FDA.

The recombinant C1 esterase inhibitor (rhC1-INH), Ruconest, was approved by the FDA in July 2014. It is indicated for adolescents and adults to treat acute attacks of HAE. Effectiveness was not established in patients with HAE that involved laryngeal attacks. Approval was supported by a phase 3 trial (n=75) that showed relief of symptoms of HAE attacks was achieved faster with rhC1-INH compared with placebo as assessed by patient questionnaire and visual analog scale.[2, 3]

Berinert and Ruconest are also approved for patient self-administration after proper training by a healthcare professional.

In December 2009, ecallantide (Kalbitor), a kallikrein inhibitor, at a dose of 30 mg SC was approved for the treatment of acute attacks.[8] A 2013 study showed that ecallantide can be safely used to treat multiple episodes of acute HAE.[28] The trial involved 147 patients who received treatment for 625 HAE episodes. Patients received ecallantide 30 mg SC for acute HAE attack symptoms, with no limit on the number of episodes treated.[28] The primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Results showed no reduction of efficacy with repeated use of ecallantide. In addition, no new safety signals were detected.[28]

In August 2011, icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved for treatment of acute attacks of HAE in adults at a dose of 30 mg SC in the abdominal area.

Purified C1-INH, fresh frozen plasma (FFP), or attenuated androgen is given prophylactically prior to surgery.

Next

Blood Products

Class Summary

These agents are used to improve the clinical aspects of the disease.

Fresh frozen plasma

 

Infuse prior to airway manipulation (eg, dental extraction) to prevent angioedema. Administering 2 units of FFP sustains complement control and prevents development of angioedema. Improved screening programs greatly reduce risk of hepatitis. FFP is not recommended for treatment of acute attacks.

Previous
Next

Androgens and Androgen Derivatives

Class Summary

Some agents in this class may increase levels of C1 inhibitor and C4 component of complement.[40, 41, 42]

Danazol (Danocrine)

 

Danazol reduces the frequency of attacks in most patients, especially those involving the airway. For prophylaxis, the dose is adjusted to lowest dose that controls symptoms.

Previous
Next

C1-Inhibitor Concentrates

Class Summary

These concentrates are used in the acute treatment of angioedema. They have recently been approved by the US FDA for routine prophylaxis against angioedema attacks and as treatment for acute attacks.

C1-inhibitor, human (Cinryze) and C1 esterase inhibitor, human (Berinert) are the same plasma protein, although for historical reasons they have been given different names. The methods of purification are somewhat different.

C1-inhibitor, human (Cinryze)

 

C1-INH is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). It regulates activation of the pathway for complement and intrinsic coagulation, and it also regulates the fibrinolytic system.

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 hereditary angioedema.

C1-INH some of the missing protein, but the 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.

C1 esterase inhibitor, human (Berinert)

 

This agent is a serine proteinase inhibitor found in human blood that regulates activation of the kinin system, complement pathway, intrinsic coagulation system, and fibrinolytic system. It binds to and neutralizes substrates that activate these systems, thereby suppressing activity. It is available as a pasteurized, lyophilized preparation derived from purified human plasma. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. C1 esterase inhibitor is indicated for acute laryngeal, abdominal, and facial angioedema attacks in adolescents and adults with HAE.

C1 esterase inhibitor recombinant (Ruconest)

 

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 hereditary angioedema (HAE). Efficacy for treatment of laryngeal attack was not established.

Previous
Next

Kallikrein Inhibitor

Class Summary

This agent has specific kallikrein inhibitor activity resulting in bradykinin reduction. It is useful for treating acute episodic attacks. 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.

Ecallantide (Kalbitor)

 

A human plasma kallikrein inhibitor, ecallantide binds to plasma kallikrein and blocks its binding site. It reduces conversion of kininogen to bradykinin. This agent is indicated for acute attacks of HAE. It is available as an injectable solution; 10 mg/mL per single-use vial.

Previous
Next

Bradykinin Receptor Antagonists

Class Summary

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).

Icatibant (Firazyr)

 

Bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE).

Previous
Next

Antifibrinolytic Agents

Class Summary

These agents act through the inhibition of plasmin. They are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.[19]

Aminocaproic acid (Amicar)

 

Aminocaproic acid is a lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances; to a lesser degree, through antiplasmin activity.

It is widely distributed. Half-life is 1-2 h. For inhibition of angioedema, several days of treatment may be required. Hepatic metabolism is minimal. This agent can be used PO/IV.

Tranexamic acid (Cyklokapron)

 

An alternative to aminocaproic acid, tranexamic acid inhibits fibrinolysis by displacing plasminogen from fibrin.

Previous
 
Contributor Information and Disclosures
Author

Michael M Frank, MD Samuel L Katz Professor of Pediatrics, Professor of Medicine and Immunology, Duke University School of Medicine, Duke University Medical Center

Michael M Frank, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Society for Pediatric Research

Disclosure: Received consulting fee from Shire for consulting; Received honoraria from Robert Michael Educationsl Institute for speaking and teaching; Received consulting fee from BioCryst for consulting.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Paul Krusinski, MD Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine

Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Amanda T Moon, MD Resident Physician, Department of Dermatology, University of Rochester, Strong Memorial Hospital

Amanda T Moon, MD, is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Medical Student Association/Foundation, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Kathleen M Rossy, MD Princeton Dermatology Associates

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, New York Academy of Medicine, and Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Michael J Wells, MD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

References
  1. Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al. When is prophylaxis for hereditary angioedema necessary?. Ann Allergy Asthma Immunol. 2009 May. 102(5):366-72. [Medline].

  2. Bankhead C. Another Drug for HAE Wins FDA Approval. MedPage Today. Jul 17 2014. [Full Text].

  3. Riedl MA, Bernstein JA, Li H, Reshef A, Lumry W, Moldovan D, 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].

  4. Starr JC, Brasher GW, Rao A, Posey D. Erythema marginatum and hereditary angioedema. South Med J. 2004 Oct. 97(10):948-50. [Medline].

  5. Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol. 2009 Jul. 124(1):129-34. [Medline].

  6. Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. 2006 Jul. 81(7):958-72. [Medline].

  7. US Food and Drug Administration (FDA). FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema. [Full Text].

  8. Zuraw B, Yasothan U, Kirkpatrick P. Ecallantide. Nat Rev Drug Discov. 2010 Mar. 9(3):189-90. [Medline].

  9. 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].

  10. 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.

  11. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):513-22. [Medline]. [Full Text].

  12. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996 Jun 20. 334(25):1630-4. [Medline].

  13. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4. 359(10):1027-36. [Medline].

  14. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009 Feb. 15(2):69-78. [Medline].

  15. Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006 Nov. 26(4):709-24. [Medline].

  16. Davis AE 3rd. Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am. 2006 Nov. 26(4):633-51. [Medline].

  17. Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005 Mar. 139(3):379-94. [Medline]. [Full Text].

  18. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006 Mar. 119(3):267-74. [Medline].

  19. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976 May. 84(5):580-93. [Medline].

  20. Nielsen EW, Gran JT, Straume B, Mellbye OJ, Johansen HT, Mollnes TE. Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses. J Intern Med. 1996 Feb. 239(2):119-30. [Medline].

  21. Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH. Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest. 1971 Oct. 50(10):2143-9. [Medline]. [Full Text].

  22. Kreuz W, Martinez-Saguer I, Aygören-Pürsün E, Rusicke E, Heller C, Klingebiel T. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion. 2009 Sep. 49(9):1987-95. [Medline].

  23. Sachse MM, Khachemoune A, Guldbakke KK, Kirschfink M. Hereditary angioedema. J Drugs Dermatol. 2006 Oct. 5(9):848-52. [Medline].

  24. Caballero T, Farkas H, Bouillet L, Bowen T, Gompel A, Fagerberg C, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012 Feb. 129(2):308-20. [Medline].

  25. Craig T et al. WAO Guideline for the Management of Hereditary Angioedema. Available at http://ainotes.wikispaces.com/file/view/WAO+Guideline+for+the+Management+of+HAE+-+2012.pdf. Accessed: February 8, 2013.

  26. Morgan BP. Hereditary angioedema--therapies old and new. N Engl J Med. 2010 Aug 5. 363(6):581-3. [Medline].

  27. US Food and Drug Administration. Advisory Committee Briefing Document:Kalbitor (ecallantide)For Acute Attacks of Hereditary Angioedema. [Full Text].

  28. Lumry WR, Bernstein JA, Li HH, Macginnitie AJ, Riedl M, Soteres DF, et al. Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: Open-label continuation study. Allergy Asthma Proc. 2013 Mar. 34(2):155-61. [Medline].

  29. Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):523-31. [Medline].

  30. Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol. 1997 Feb. 99(2):194-6. [Medline].

  31. Krause K, Metz M, Zuberbier T, Maurer M, Magerl M. Successful treatment of hereditary angioedema with bradykinin B2-receptor antagonist icatibant. J Dtsch Dermatol Ges. 2010 Apr. 8(4):272-4. [Medline].

  32. Bouillet L, Boccon-Gibod I, Ponard D, Drouet C, Cesbron JY, Dumestre-Perard C, et al. Bradykinin receptor 2 antagonist (icatibant) for hereditary angioedema type III attacks. Ann Allergy Asthma Immunol. 2009 Nov. 103(5):448. [Medline].

  33. 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].

  34. Bracho FA. Hereditary angioedema. Curr Opin Hematol. 2005 Nov. 12(6):493-8. [Medline].

  35. Zuraw BL. Current and future therapy for hereditary angioedema. Clin Immunol. 2005 Jan. 114(1):10-6. [Medline].

  36. Zuraw BL. Novel therapies for hereditary angioedema. Immunol Allergy Clin North Am. 2006 Nov. 26(4):691-708. [Medline].

  37. American Academy of Allergy, Asthma & Immunology. Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help. J Allergy Clin Immunol. 2006 Feb. 117(2 Suppl Consultation):S495-523. [Medline].

  38. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, 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].

  39. Bork K, Witzke G. Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol. 1989 Mar. 83(3):677-82. [Medline].

  40. Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol. 1991 Apr. 87(4):768-73. [Medline].

  41. Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med. 1976 Dec 23. 295(26):1444-8. [Medline].

  42. Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol. 1981 Sep. 68(3):181-7. [Medline].

  43. A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3). [Full Text].

  44. Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000 Jul 15. 356(9225):213-7. [Medline].

  45. EASSI - Evaluation of the Safety of Self-Administration With Icatibant. [Full Text].

  46. Johnson K. Real-world use of icatibant improves angioedema. Medscape Medical News. November 12, 2013. [Full Text].

  47. Leiden, The Netherlands. Biotech company Pharming Group NV ("Pharming" or "the Company") (NYSE Euronext: PHARM) today announces that, in agreement with the European Medicines Agency (EMEA), the dossier for the European Marketing Authorisation Application (MAA) of Rhucin(R) will be submitted in September 2009. [Full Text].

  48. Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011 Dec. 107(6):529-37. [Medline].

  49. Maurer M, Aberer W, Bouillet L, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One. 2013. 8(2):e53773. [Medline]. [Full Text].

  50. Riedl M, Longhurst H, Fabien V, Lumry WR, Maurer M. Icatibant for the treatment of non-laryngeal hereditary angioedema attacks: comparison of outcomes from a controlled phase III trial and a real-world setting (abstract P85). Presented at: The American College of Allergy, Asthma & Immunology (ACAAI) 2013 Annual Scientific Meeting; November 9, 2013; Baltimore, Maryland.

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.