C1-Esterase Inhibitor (Human)
Class: Complement Inhibitors
Brands: Berinert, Cinryze
C1-esterase inhibitor is a naturally occurring inhibitor of certain serine proteases (e.g., C1 complement, kallikrein, coagulation factor XIIa, plasmin) involved in the complement, coagulation (contact), and fibrinolytic systems.1 2 4 5 6 7 8 10 11 12 19 21
Uses for C1-Esterase Inhibitor (Human)
Hereditary Angioedema: Prevention of Angioedema Attacks
One of several agents that may be considered for long-term prophylaxis of HAE attacks; other drugs include attenuated androgens (e.g., danazol) and antifibrinolytic agents (e.g., tranexamic acid).2 5 6 8 9 11 12 13 19 26 27 36
Consider long-term prophylaxis in patients with HAE who have frequent or severe attacks of angioedema; individualize need for prophylactic therapy based on factors such as severity of disease, frequency of attacks, patient's quality of life, availability of resources, and patient response to on-demand therapy.2 5 6 11 12 13 15 16 19 27 36
Hereditary Angioedema: Treatment of Acute Angioedema Attacks
Recommended by US and international consensus guidelines as one of several options for treatment of acute HAE attacks; other drugs include ecallantide (plasma kallikrein inhibitor) and icatibant (bradykinin B2-receptor antagonist).24 26 27 29 32 36
C1-Esterase Inhibitor (Human) Dosage and Administration
Reconstitution of Cinryze
Reconstitute vial of Cinryzecontaining 500 units of C1-esterase inhibitor (human) with 5 mL of sterile water for injection using transfer set provided by manufacturer or another commercially available double-ended needle; vacuum will draw in the diluent.1 Do not use vials that lack a vacuum.1 Gently swirl until powder is completely dissolved.1 Resultant solution contains 100 units/mL and should be colorless to slightly blue, and free from visible particles.1 Reconstitute 2 vials to obtain a single 1000-unit dose.1
Manufacturer recommends that silicone-free syringes be used for reconstitution and administration of Cinryze.1
Administer within 3 hours of reconstitution.1
Reconstitution of Berinert
Allow vials of drug and diluent (sterile water for injection) to reach room temperature prior to reconstitution.21
Reconstitute vial of Berinert containing 500 units of C1-esterase inhibitor (human) with 10 mL of sterile water for injection using transfer set provided by manufacturer or another commercially available double-ended needle and vented filter spike.21 Gently swirl vial to ensure complete dissolution.21 Resultant solution should be colorless, clear, and free from visible particles.21
Administer within 8 hours of reconstitution.21
Rate of Administration
Cinryze: Administer IV over 10 minutes at a rate of approximately 1 mL/minute.1
Berinert: Administer IV at a rate of approximately 4 mL/minute.21
Dosage of C1-esterase inhibitor (human) is expressed in international units (IU, units).1 21 One unit of C1-esterase inhibitor (human) is equivalent to the mean concentration of C1-esterase inhibitor present in 1 mL of normal fresh human plasma.1 5 8 21
Routine Prophylaxis of Angioedema AttacksIV
Cinryze: Adolescents 13–18 years of age: 1000 units every 3–4 days.1 20 Some clinicians recommend that the frequency of administration be individualized using the lowest possible frequency to prevent acute attacks.5
Treatment of Angioedema AttacksIV
Routine Prophylaxis of Angioedema AttacksIV
Cinryze: 1000 units every 3–4 days.1 Other dosing frequencies (e.g., every 5–7 days) have been used.5 9 13 15 Some clinicians recommend that frequency of administration be individualized using the lowest possible frequency to prevent acute attacks.5
Treatment of Angioedema AttacksIV
Cautions for C1-Esterase Inhibitor (Human)
Risk of Transmissible Agents in Plasma-derived Preparations
Potential vehicle for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], HBV, HCV, parvovirus B19) or other infectious agents (e.g., Creutzfeldt-Jakob disease [CJD]).1 9 12 13 21 Risk substantially reduced with current donor screening practices and viral inactivating procedures; however, possibility of disease transmission still exists.1 12 15 19 21
Although cases of suspected viral transmission (including HCV) have been reported with use of Berinert outside the US, manufacturer states no causal relationship to the drug has been established since introduction of a pasteurization step in 1985.21
Weigh risks of viral infection against benefits of therapy.1 12 21 Some experts recommend that patients who receive long-term treatment with blood products be vaccinated against hepatitis A and hepatitis B.12 13 Report any suspected infections thought to be associated with C1-esterase inhibitor (human) to the manufacturer.1 21
Because of potential for airway obstruction, patients who self-administer C1-esterase inhibitor (human) for treatment of a laryngeal attack should seek immediate medical attention in an appropriate healthcare facility after the drug is administered.21
Potential for immunogenicity with use of all therapeutic proteins, including C1-esterase inhibitor (human).1 Development of noninhibitory antibodies to C1-esterase inhibitor (human) reported in clinical trials; however, clinically important effects not observed.1 38 39
Risk of severe hypersensitivity reactions (e.g., hives, urticaria, chest tightness, wheezing, hypotension, anaphylaxis).1 21 If hypersensitivity occurs, discontinue drug immediately and initiate appropriate treatment.1 21 Because symptoms of hypersensitivity can resemble acute attacks of hereditary angioedema, carefully consider treatment method.1 21 Epinephrine should be available for immediate use.1 21
Safety and efficacy of Berinert not established in pediatric patients ≤12 years of age, although used successfully for the treatment of acute HAE attacks in a limited number of children as young as 6 years of age.21 25 37
Common Adverse Effects
Interactions for C1-Esterase Inhibitor (Human)
C1-Esterase Inhibitor (Human) Pharmacokinetics
Plasma concentrations of C1-esterase inhibitor increase immediately (i.e., within 1 hour) following IV administration; C4 levels subsequently rise 2–24 hours later, indicating consumption of C1-esterase inhibitor and stabilization of the complement activation system.1 5 6 8 15
Not known whether C1-esterase inhibitor is distributed into milk.1
Berinert: Following administration of single doses (500–1500 units) in patients with mild to severe HAE, half-life approximately 18 hours in adults and 17 hours in pediatric patients 6–13 years of age.21
Difference in half-life observed between Cinryze and Berinert may be due to differences in patient populations evaluated (e.g., asymptomatic versus symptomatic).34
Limited data on Berinert suggest that half-life of C1-esterase inhibitor (human) may be decreased and clearance increased in pediatric patients <12 years of age compared with adults; clinical importance of such findings not known.21
Powder for Injection
Naturally occurring serine protease inhibitor that principally regulates the activation of the complement and intrinsic coagulation (e.g., contact system) pathways.1 2 4 5 6 7 8 10 11 12 19 21 Also plays a role in the fibrinolytic system.1 2 6 8 12 21
Regulates contact system activation by inhibiting plasma kallikrein and coagulation factor XIIa; such actions prevent formation of bradykinin, the presumed mediator of increased vascular permeability in HAE.1 2 4 5 6 7 10 11 12 13 21
Preparation of highly purified C1-esterase inhibitor derived from pooled human plasma.1 8 19 21 Undergoes a series of viral reduction steps (e.g., pasteurization, precipitation, nanofiltration, chromatography) to reduce risk of viral transmission.1 8 19 21
Advice to Patients
Importance of clinicians providing clear instructions and training on proper IV administration technique to patients self-administering C1-esterase inhibitor (human).21 Advise patients to record the lot number of the C1-esterase inhibitor (human) vial used each time they self-administer the drug.1 21
Importance of patients not starting self-administration if an HAE attack has progressed to a point where the patient or caregiver is unable to successfully prepare or administer the drug.21
After self-administering the drug to treat an acute laryngeal attack of HAE, importance of seeking immediate medical attention in an appropriate healthcare facility because of the potential for airway obstruction during such attacks.21
After self-administering the drug to treat a suspected abdominal HAE attack, importance of contacting clinician to rule out the possibility of other potentially serious causes.21
Risk of transmission of human viruses (i.e., HAV, HBV, HCV, HIV, parvovirus B19) and other infectious agents (i.e., causative agent for Creutzfeldt-Jakob disease).1 12 21 Advise patient that current donor screening and viral inactivating procedures have reduced, but not completely eliminated, the risk of disease transmission.1
Importance of discontinuing therapy and immediately informing clinician if any signs or symptoms of hypersensitivity (e.g., rash, hives, chest tightness, wheezing, hypotension, anaphylaxis) occur.1 21
Risk of thrombotic events; advise patients to immediately report any signs and symptoms of thrombosis (e.g., new-onset swelling and pain in the limbs or abdomen; new-onset chest pain; shortness of breath; loss of sensation or motor ability; altered consciousness, vision, or speech).21
Advise patients to bring their drug with them when visiting a healthcare provider or facility for an acute HAE attack.21
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
For injection, for IV infusion
AHFS DI Essentials. © Copyright 2017, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. VioPharma. Cinryze (C1 inhibitor, human) prescribing information. Exton, PA; 2012 Nov.
2. Zuraw BL. Hereditary angioedema. N Engl J Med. 2008; 359:1027-36. [PubMed 18768946]
3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [May 5, 2003]. From FDA web site.
4. Maplethorpe C. C1 inhibitor (human) clinical review. Rockville, MD: Food and Drug Administration; 2008 Oct 20.
5. Prematta MJ, Prematta T, Craig TJ. Treatment of hereditary angioedema with plasma-derived C1 inhibitor. Ther Clin Risk Manag. 2008; 4:975-82. [PubMed 19209279]
6. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001; 161:2417-29. [PubMed 11700154]
7. Caliezi C, Wuillemin WA, Zeerleder S et al. C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev. 2000; 52:91-112. [PubMed 10699156]
8. US Food and Drug Administration. Briefing document from the blood products advisory committee. May 2, 2008. From FDA website (http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4355B2-2.pdf).
9. Levi M, Choi G, Picavet C et al. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol. 2006; 117:904-8. [PubMed 16630950]
10. Frank MM. 8. Hereditary angioedema. J Allergy Clin Immunol. 2008; 121:S398-401; quiz S419.
11. 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; 83:677-82. [PubMed 2926086]
12. Gompels MM, Lock RJ, Abinun M et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005; 139:379-94. [PubMed 15730382]
13. Bowen T, Cicardi M, Bork K et al. Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008; 100 (Supp 2):S30-40.
14. Temiño VM, Peebles RS. The spectrum and treatment of angioedema. Am J Med. 2008; 121:282-6. [PubMed 18374684]
15. Frank MM, Jiang H. New therapies for hereditary angioedema: disease outlook changes dramatically. J Allergy Clin Immunol. 2008; 121:272-80. [PubMed 18206518]
16. Farkas H, Varga L, Széplaki G et al. Management of hereditary angioedema in pediatric patients. Pediatrics. 2007; 120:e713-22.
17. Horstick G, Berg O, Heimann A et al. Application of C1-esterase inhibitor during reperfusion of ischemic myocardium: dose-related beneficial versus detrimental effects. Circulation. 2001; 104:3125-31. [PubMed 11748112]
18. Zuraw B, Busse P, White M et al. Efficacy and safety of long term prophylaxis with C1 inhibitor (C1INH) concentrate in patients with hereditary angioedema. J Allergy Clin Immunol. 2008; 21:S272, Abstract 1049.
19. Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008; 68:2561-73.
20. ViroPharma: Personal communication.
21. CSL Behring. Berinert (C1 esterase inhibitor, human) prescribing information. Kankakee, IL; 2012 July.
22. Craig TJ, Levy RJ, Wasserman RL et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009; 124:801-8. [PubMed 19767078]
23. Food and Drug Administration. Summary Basis for Regulatory Action: B:A Supplement#STN 125287/110. From FDA website.
24. Thomas MC, Shah S. New treatment options for acute edema attacks caused by hereditary angioedema. Am J Health Syst Pharm. 2011; 68:2129-38. [PubMed 22058099]
25. Farkas H, Csuka D, Zotter Z et al. Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients. J Allergy Clin Immunol. 2013; 131:909-11. [PubMed 23063583]
26. Lang DM, Aberer W, Bernstein JA et al. International consensus on hereditary and acquired angioedema. Ann Allergy Asthma Immunol. 2012; 109:395-402. [PubMed 23176876]
27. Zuraw BL, Bernstein JA, Lang DM et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013; 131:1491-3. [PubMed 23726531]
28. Gandhi PK, Gentry WM, Bottorff MB. Thrombotic events associated with C1 esterase inhibitor products in patients with hereditary angioedema: investigation from the United States Food and Drug Administration adverse event reporting system database. Pharmacotherapy. 2012; 32:902-9. [PubMed 23033229]
29. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012; 379:474-81. [PubMed 22305226]
30. Zuraw BL, Busse PJ, White M et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010; 363:513-22. [PubMed 20818886]
31. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996; 334:1630-4. [PubMed 8628358]
32. . Three new drugs for hereditary angioedema. Med Lett Drugs Ther. 2010; 52:66-7. [PubMed 20724964]
33. Wasserman RL, Levy RJ, Bewtra AK et al. Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2011; 106:62-8. [PubMed 21195947]
34. Bernstein JA, Ritchie B, Levy RJ et al. Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2010; 105:149-54. [PubMed 20674826]
35. Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med. 2001; 161:714-8. [PubMed 11231704]
36. Craig T, Aygören-Pürsün E, Bork K et al. WAO Guideline for the Management of Hereditary Angioedema. World Allergy Organ J. 2012; 5:182-99. [PubMed 23282420]
37. Schneider L, Hurewitz D, Wasserman R et al. C1-INH concentrate for treatment of acute hereditary angioedema: a pediatric cohort from the I.M.P.A.C.T. studies. Pediatr Allergy Immunol. 2013; 24:54-60. [PubMed 23173714]
38. Craig TJ, Bewtra AK, Bahna SL et al. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study. Allergy. 2011; 66:1604-11. [PubMed 21884533]
39. Craig TJ, Bewtra AK, Hurewitz D et al. Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks. Allergy Asthma Proc. 2012 Jul-Aug; 33:354-61.