Hereditary angioedema treatment options: The availability of new therapies

Figures & data

Figure 1. Simplified schematic of the biological cascades, regulated by C1-INH, which lead to oedema, indicating which stage each treatment option targets (13). Adapted by permission from Macmillan Publishers Ltd: Zuraw et al. Nat Rev Drug Discov 2010;9(3):189–190, copyright 2010. Abbreviations: C1-INH = C1-inhibitor; HMMK = high-molecular mass kininogen; BK = bradykinin.

Figure 2. Treatment options with licensed and non-licensed indications for HAE.

*Cinryze^® licensed for prophylaxis; some clinicians prescribe Berinert^® off-label for this purpose.

Table I. Overview of treatments available.

	Mode of action	Date of approval in Europe (EMA)	Licensed indication	Dosage	Considerations
PROPHYLAXIS
Attenuated androgens (e.g. danazol / stanozolol)	Stimulates production of C1-INH	N/A^a	Not licensed for HAE (but commonly prescribed for prophylaxis)	Maximum long-term dose of 200 mg daily for danazol and 2 mg daily for stanozolol	Administered orally Serious side-effects including weight gain, virilization, menstrual irregularities, muscle pains and cramps, headaches, hepatic toxicity (25) Contraindicated in children and pregnant women and during lactation
Antifibrinolytics (e.g. tranexamic acid)	Inhibits plasmin, thereby reducing C1-INH consumption	1983	Short-term use for haemorrhage or risk of haemorrhage in increased fibrinolysis or fibrinogenolysis. Local fibrinolysis as occurs in the following conditions: HAE (26)	20–50 mg/kg/day	Administered orally Side-effects include dyspepsia, myalgia, muscle weakness, hypotension, fatigue, retinal changes (14) Contraindicated during lactation; use with restrictions during pregnancy (27)
pdC1-INH (Cinryze^®)**	Replacement C1-INH	2011	Routine prevention of angioedema attacks in adults and adolescents with severe and recurrent attacks of HAE, who are intolerant to or insufficiently protected by oral prevention treatments, or patients who are inadequately managed with repeated acute treatment (28)	1000 U every 3 or 4 days. The dosing interval may need to be adjusted according to individual response	Administered i.v. Licensed for self-administration
ACUTE TREATMENT
pdC1-INH (Berinert^®)**	Replacement C1-INH	1979 (Current formulation since 1990)	Treatment of acute abdominal or facial HAE attacks in adult and adolescent patients The safety and efficacy of Berinert^® for prophylactic therapy have not been established (29)	20 U/kg	Administered i.v. Licensed for self-administration
pdC1-INH (Cetor^®/Cebitor^®)**	Replacement C1-INH	1997 (approved in the Netherlands)	Intended for use in cases of congenital C1-INH deficiency in the acute treatment of angioedema in adult and adolescent patients (30)	1000 U	Administered i.v. Licensed for self-administration
pdC1-INH (Cinryze^®)**	Replacement C1-INH	2011	Treatment and pre-procedure prevention of angioedema attacks in adults and adolescents with HAE (28)	1000 U	Administered i.v. Licensed for self-administration
rhC1-INH (Ruconest^®)**	Replacement C1-INH	2010	Treatment of acute angioedema attacks in adults with HAE due to C1-INH deficiency (31)	50 U/kg in adults < 84 kg body weight; 4200 U in adults ≥ 84 kg body weight)	Administered i.v. Not licensed for self-administration Should not be used in patients with a known or suspected allergy to rabbits
Icatibant (Firazyr^®)**	Bradykinin B2 receptor blockade	2008	Symptomatic treatment of acute attacks of HAE in adults (32)	30 mg	Administered s.c. Licensed for self-administration
Ecallantide (Kalbitor^®)**	Kallikrein inhibitor	Application withdrawn	Treatment of acute attacks of HAE in patients 16 years of age and older (17)	30 mg	Administered s.c. Not licensed in the EU Risk of anaphylaxis

^aMay be approved nationally, e.g. danazol is licensed in Austria for prophylactic treatment.

**Although the wording in each product SPC differs, the general advice for these products it to only use during pregnancy if the potential benefit justifies the potential risk to the foetus, and caution should be exercised when administering to nursing women (17,28–32).

Zuraw B, Yasothan U, Kirkpatrick P. Ecallantide. Nat Rev Drug Discov. 2010;9:189–90.

 PubMed Web of Science ®Google Scholar

Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, . C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139:379–94.

 PubMed Web of Science ®Google Scholar

Cyklokapron summary of product characteristics. Available from: http://www.medicines.org.uk/emc/medicine/16512/SPC/ (accessed 17 August 2011).

 Google Scholar

Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, . 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6:24.

 Google Scholar

Caballero T, Farkas H, Bouillet L, Bowen T, Gompel A, Fagerberg C, . 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;129:308–20.

 PubMed Web of Science ®Google Scholar

Cinryze summary of product characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001207/WC500108895.pdf (accessed 15 July 2011).

 Google Scholar

Berinert prescribing information. Available from: http://www.berinert.com/docs/Berinert_pi.pdf (accessed 15 July 2011).

 Google Scholar

Cetor summary of product characteristics. Available from: http://www.sanquin.nl/sanquin-eng/sqn_products_plasma.nsf/All/F197E/$FILE/common-spc-summaryofproductcharacteristicscetor500uen.pdf (accessed 15 July 2011).

 Google Scholar

Ruconest summary of product characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001223/WC500098542.pdf (accessed 15 July 2011).

 Google Scholar

Firazyr summary of product characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000899/WC500022966.pdf (accessed 15 July 2011).

 Google Scholar

Kalbitor prescribing information. Available from: http://www.kalbitor.com/pdf/KalbitorFullPrescribingInformation.pdf (accessed 15 July 2011).

 Google Scholar