Hereditary Angioedema Medication

Updated: Jul 27, 2016
  • Author: Michael M Frank, MD; Chief Editor: Michael A Kaliner, MD  more...
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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. Use was expanded to include children younger than 12 years in July 2016.

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.


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.


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.


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 children 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.


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.


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).


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.