Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance

Figures & data

Figure 1 Pathways inhibited by C1-INH.

Notes: Horizontal bars over the complement names indicate activation. Copyright © 2014. Future Medicine Ltd. Reproduced from Bork K. Pasteurized and nanofiltered, plasma-derived C1 esterase inhibitor concentrate for the treatment of hereditary angioedema. Immunotherapy. 2014;6(5):533–551.¹¹
Abbreviations: C1-INH, C1 esterase inhibitor; FXI, factor XI; FXIa, activated factor XI; FXII, factor XII; FXIIa, activated factor XII; HMWK, high molecular weight kininogen; MASP, mannose-binding lectin-associated serine protease; tPA/uPA, tissue/urokinase plasminogen activator.

Table 1 Approval status of intravenously delivered human plasma-derived C1-INH concentrates for treatment of or prophylaxis against acute HAE attacks

Trade name (company)	Approval status	Dosage	Storage and plasma half-life in adults	Administration
Berinert^® (CSL Behring)	EU: approved in April 2013 for short-term prophylaxis only^Citation32 FDA: approved in October 2009 for acute facial and abdominal attacks only^Citation33	20 IU/kg	Lyophilized and stored at 2°C–25°C; 32–47 hours	For >12 years and <65 years of age; can be self-administered or administered at home
Cinryze^® (Shire ViroPharma Incorporated)	EU: approved in June 2011 for acute attacks, short-term, and long-term prophylaxis^Citation34 FDA: approved in October 2008 for long-term prophylaxis^Citation35	1,000 U every 3–4 days; infusion rate 1 mL/min	Lyophilized and stored at 2°C–25°C; 48±10 hours	In adults and adolescents only (>12 years of age); can be self-administered or administered at home
Cetor^® (Sanquin)	EU: approved in 1997 in the Netherlands, Belgium, Finland, France, and Luxembourg only for acute attacks^Citation36 FDA: not approved	1,000 U	Lyophilized and stored at 2°C–8°C; 48±10 hours	In adults and adolescents only (>12 years of age); can be self-administered or administered at home

Notes: Short-term prophylaxis refers to prophylaxis before surgical or dental procedures. Long-term prophylaxis refers to routine prevention. “For acute attacks” means on-demand treatment.

Abbreviations: C1-INH, C1 esterase inhibitor; EU, European Union; FDA, US Food and Drug Administration; HAE, hereditary angioedema.

Table 2 Summary of real-world observational data for home-based HAE therapy with human plasma-derived C1-INH

Drug name	Prior preventative medicine	Number of patients in study	Observational study findings of home therapy	References
Berinert^®	Danazol	22 with severe symptoms and incompatibility or lack of response to danazol	Median number of attacks/year decreased (P<0.001) 24 laryngeal episodes/year ceased No viral transmission	Kreuz et al^Citation51
Berinert	Physician-administered Berinert	15 pediatric (on-demand treatment) and five pediatric (prophylaxis)	Significant increase in dosing frequency All attacks including laryngeal edema treated Mean days hospitalized reduced from 3.8 to 0.11/year No side effects or injection site reactions Median time between attack onset and administration reduced from 67.5 to 15 minutes TOSR reduced from 60 to 40 minutes	Kreuz et al^Citation55
Berinert	Danazol and/or tranexamic acid	Seven with severe or frequent symptoms	After 3–48 months, improved quality of life, DLQI score reduced from 12.6 to 2.7 (P<0.001), improved SF-36 scores No serious complications at 27–72 months, follow-up	Bygum et al^Citation56
Cetor^®	Danazol and/or tranexamic acid	31 on-demand treatment (28 with HAE, three with AAE-C1-INH) and 12 prophylaxis (ten with HAE, two with AAE-C1-INH)	All patients capable of intravenous self-administration Technical failure rate <2% Significantly shorter TOSR (2.2 hours) In prophylaxis group, attack rate decreased from 4 to 0.3 per month	Levi et al^Citation54

Abbreviations: AAE-C1-INH, acquired angioedema due to C1 esterase inhibitor deficiency; C1-INH, C1 esterase inhibitor; DLQI, Dermatology Life Quality Index; HAE, hereditary angioedema; SF-36, 36-Item Short-Form Health Survey; TOSR, time to onset of symptom relief.

Table 3 Treatment-related AEs associated with commercially available human plasma-derived C1-INH concentrates for HAE treatment

AEs	Berinert^®	Cinryze^®	Cetor^®
Allergic or hypersensitivity reactions	Includes hives, generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis	Allergic reactions that may occur include wheezing, difficulty breathing, chest tightness, cyanosis (lips and gums), tachycardia, facial swelling, faintness, rash, hives (use is not recommended if the patient has experienced a life-threatening immediate hypersensitivity reaction to the product, including anaphylaxis)	Tachycardia, hyper- or hypotension, flushing, hives, dyspnea, headache, dizziness, nausea, anaphylaxis
Serious events	Arterial and venous thromboembolic events	Arterial and venous thromboembolic events, cerebrovascular accidents	Hypersensitivity or anaphylactic shock
Plasma-derived risks	Risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt–Jakob disease agent	Risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt–Jakob disease agent	Risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt–Jakob disease agent (only one viral removal step in purification process) Physician may recommend hepatitis A or B vaccination if this product is administered frequently
Most serious	Increase in the severity of HAE-associated pain		Reaction at injection site, rise in temperature (classified as rare)
Most common	Dysgeusia (>4% of patients and more frequently than in the placebo group)	Headache, nausea, rash, and vomiting	All considered mild and rare
Additional risks	Has not been evaluated in pregnant women or nursing mothers, and safety and efficacy have not been established in children (0–12 years of age) or in the geriatric population	Has not been evaluated in pregnant women or nursing mothers Risk associated if taking contraceptive pills or androgens Safety and efficacy not established in children (0–11 years of age)	Has not been evaluated in pregnant women or nursing mothers No studies on the ability to drive or operate machines post administration Safety and efficacy not established in children (0–11 years of age)
References	Berinert safety information^Citation70	Cinryze safety information^Citation71 Cinryze prescribing information^Citation38	Cetor summary of product characteristics^Citation72 Cetor package leaflet^Citation73

Abbreviations: AE, adverse event; CI-INH, C1 esterase inhibitor; HAE, hereditary angioedema.

Table 4 Patient eligibility criteria for home-based HAE treatment

Factor	Patient criteria for home therapy	References
Nature of HAE	CI-INH deficiency	Gompels et al^Citation16
Severity and frequency of attacks	Severe or frequent symptoms	Kreuz et al;^Citation51 Bygum et al^Citation56
Efficacy or tolerability of current prophylactic therapies	Incompatibility or lack of response to danazol or tranexamic acid	Kreuz et al;^Citation51 Levi et al^Citation54
Current effect of HAE on quality of life	Serious and affected by delay in visiting emergency departments in the event of an attack	Bygum et al^Citation56
Expectations	Managed via education, training, and support	Longhurst et al^Citation58
Mental or physical capacity	Essential for self-administration
Compliance or reliability	Should be optimal	Gompels et al^Citation16
Maintaining infusion skill set	Infusion required at least once every 3 months	Gompels et al^Citation16
Consent	Should be obtained in written format	Gompels et al^Citation16
Awareness of risk	Informed of risk of transmissible infection from a plasma-derived product	Gompels et al^Citation16
Partner or caregiver	Available at the time of treatment (particularly important if age or disability is a factor)	Gompels et al^Citation16 Gower et al^Citation84
Local family practice support	Written confirmation of support from general practitioner, including preplanned emergency care if required	Gompels et al^Citation16
Communication access	Close proximity of a telephone when administering treatment	Gompels et al^Citation16
Venous access	Good venous access (current approved treatments are intravenous)	Gompels et al^Citation16
Plan of action if administration is difficult	Agreement by patient to call the emergency service if self-cannulation is unsuccessful at the time of the HAE attack	Gompels et al^Citation16
Physician’s risk–benefit judgement	Do the benefits of home therapy outweigh the risks and possible side effects for the patient?	Cicardi et al^Citation61

Note: Copyright © 2005. British Society for Immunology. John Wiley and Sons. Adapted from Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005; 139(3):379–394.¹⁶

Abbreviations: CI-INH, C1 esterase inhibitor; HAE, hereditary angioedema.

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