Acquired Angioedema Due to C1 Inhibitor Deficiency Medication

Updated: May 20, 2020
  • Author: Amanda T Moon, MD; Chief Editor: William D James, MD  more...
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Medication

Medication Summary

The goals of pharmacotherapy for acquired angioedema 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 the treatment of acute attacks of angioedema in hereditary angioedema (HAE) patients for decades, and it is now available in the United States. 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/wk for prophylaxis to prevent HAE 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. Berinert was also approved for acute treatment of laryngeal attacks in January 2012.

In acquired angioedema, therapy for acute attacks may also be aborted with C1-INH concentrates. [15, 16] In one study of 44 patients with C1-INH–deficient AAE, treatment with plasma-derived C1-INH concentrate consistently decreased the duration of attacks compared with nontreatment. [15] Although there is wide variability in the degree of responsiveness, the findings are true even when a patient has autoantibodies against C1-INH. Rapid catabolism of C1-INH occurs in acquired angioedema and may require higher doses of C1-INH plasma concentrate compared with HAE. If C1-INH concentrate is unavailable, fresh-frozen plasma can be used.

In June 2017, the FDA approved the first subcutaneous C1 esterase inhibitor (Haegarda) for prevention of HAE attacks in patients aged 12-72 years. Approval was based on the phase 3 COMPACT trial (n=90), which showed C1-INH 60 IU twice weekly SC reduced the median number of HAE attacks by 90% compared with placebo. The study also showed use of rescue medication was reduced by greater than 99% versus placebo. [17]

In December 2009, ecallantide (Kalbitor), a kallikrein inhibitor, at a dose of 30 mg SC was approved for the treatment of acute attacks.

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. It is highly effective in decreasing the duration of attacks of acquired angioedema and was reported to successfully treat 26 of 26 patients. [16]

Androgens, such as danazol, may be beneficial in acquired angioedema type I, with one study reporting effective treatment of 23 (75%) of 31 patients. [16] Androgens are of no value in acquired angioedema type II. Prostate cancer and pregnancy preclude the use of androgens.

Antifibrinolytics, such as epsilon-aminocaproic acid and tranexamic acid, have been found to be more effective for long-term prophylaxis in those with acquired angioedema, although tranexamic acid has moderate efficacy as an abortive as well. [16]

Immunosuppressive therapy directed toward decreasing autoantibody production may be of value in patients with acquired angioedema type II, which may be accomplished by the use of plasmapheresis with cyclophosphamide.

In 2004 and 2006, two papers reported effective treatment of acquired angioedema cases with a series of 4 weekly injections with rituximab (a chimeric monoclonal antibody to CD20). In one study, rituximab treatment resulted in normalization of C1-INH and C4 levels and long-term remission of angioedema attacks in 3 patients with severe acquired angioedema. [18] In the second study, a patient with acquired angioedema type II refractory to standard treatment experienced a 6-month attack-free interval after treatment with rituximab. [19] Several other reports have supported the efficacy of rituximab in achieving remission of acquired angioedema in patients with either an underlying B-cell lymphoproliferative disorder or autoimmune disease. [20, 21, 22, 23] A long-term study of 10 patients over 10 years showed that rituximab decreased the number of attacks and increased the amount of C1-INH in patients with C1-INH–deficient acquired angioedema. [24]

Another immunosuppressant drug, etanercept, was reported to control angioedema in a 57-year old man with psoriatic arthritis. This man was treated with 25 mg of etanercept administered subcutaneously twice per week for recalcitrant psoriatic arthritis. The treatment also resulted in improvement of the patient's angioedema. The authors hypothesized that etanercept may have improved the angioedema by decreasing inflammation and vascular permeability. [25]

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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 fresh frozen plasma (FFP) sustains complement control and prevents the development of angioedema. Improved screening programs greatly reduce risk of hepatitis. FFP is not recommended for treatment of acute attacks.

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Alkylating Agents

Class Summary

Some agents in this class have potent immunosuppressive activity.

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

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C1-Inhibitor Concentrates

Class Summary

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 regulates the fibrinolytic system. Depending on the particular brand, these concentrates are used in the acute treatment of angioedema. They are approved by the US FDA for routine prophylaxis against angioedema attacks and as treatment for acute attacks.

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 inhibitor human (Berinert, Cinryze, Haegarda)

This agent is aerine proteinase inhibitor that increases the plasma concentration of C1 inhibitor activity. Berinert is indicated for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults and children. Cinryze and Haegarda are indicated for routine prophylaxis in adults and adolescents. Berinert and Cinryze are administered as an intravenous infusion, whereas Haegarda is administered as a subcutaneous injection.

C1 esterase inhibitor recombinant (Ruconest)

This agent is a human recombinant C1 esterase inhibitor purified 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 the treatment of acute HAE attacks in adults and adolescents. It is administered as an intravenous infusion over 5 minutes.

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Kallikrein Inhibitors

Class Summary

These agents have specific kallikrein inhibitor activity, resulting in bradykinin reduction. They are 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 drugs. They 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 the 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.

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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)

Icatibant is a bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE).

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Androgens and Androgen Derivatives

Class Summary

These agents have immunosuppressive properties.

Danazol

Danazol increases levels of the C4 component of complement and prevents attacks associated with angioedema.

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Antifibrinolytic Agents

Class Summary

Antifibrinolytic agents act through the inhibition of plasmin. They tend to be more effective than androgens for prophylaxis.

Aminocaproic acid (Amicar)

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

This agent is widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal. It can be used PO or IV.

Tranexamic acid (Cyklokapron, Lysteda)

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

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Antineoplastics, Anti-CD20 Monoclonal Antibodies

Class Summary

The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

Rituximab (Rituxan)

Rituximab is a humanized monoclonal antibody. It binds to the CD20 antigen, inducing complement- or antibody-mediated cytolysis. Variable treatment regimens have been used to treat acquired angioedema.

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