On-Demand Therapies for HAE Attacks

Written by Margaret Anne Rockwood | Last updated September 10th, 2026
Medically reviewed by Timothy J. Craig, DO

Targeted therapies have transformed the acute management of hereditary angioedema (HAE) by directly interrupting the bradykinin pathway or replacing deficient C1 inhibitor. Intravenous C1-INH replacement, plasma kallikrein inhibition, and bradykinin receptor antagonism provide effective treatment when administered promptly.

Prompt treatment of an attack is essential to minimize symptom severity, shorten attack duration, and reduce the risk of life-threatening complications. Patients should have immediate access to at least two doses of on-demand medication and be educated in self-administration whenever feasible.

How to Recognize Acute HAE

Common clinical presentations of an acute HAE attack are described below.

Cutaneous attacks: Peripheral swelling is often painful, tense, and functionally disabling rather than pruritic. Patients frequently report difficulty walking, grasping objects, or performing routine occupational tasks.

Erythema marginatum: A characteristic annular, serpiginous rash may precede attacks in some patients and is frequently mistaken for urticaria.

Gastrointestinal attacks: Abdominal attacks are among the most debilitating manifestations of HAE and may occur in isolation.

Laryngeal attacks: Although less common than peripheral or abdominal attacks, laryngeal edema represents the most feared complication of HAE because of the potential for airway obstruction and asphyxiation.

See more detail on multisystem manifestations.

Without prompt recognition and appropriate treatment, laryngeal attacks can become life-threatening. Patients may experience attacks at different intervals, ranging from none to a few attacks a year, to weekly attacks. However, attack frequency alone does not reliably predict disease severity, as even patients with otherwise infrequent attacks remain at risk for life-threatening airway involvement.

Common Triggers

Although HAE attacks may occur spontaneously, several factors can precipitate episodes. Frequently reported triggers include:

• emotional stress
• minor trauma
• dental procedures
• surgery
• upper respiratory infections
• medical procedures such as endoscopy
• hormonal changes, including menstruation and pregnancy
• estrogen-containing contraceptives or hormone replacement therapy
• angiotensin-converting enzyme (ACE) inhibitors

Many individuals living with HAE are unable to identify a consistent trigger for every attack.

Treatment Options

Unlike histamine-mediated angioedema, HAE attacks are bradykinin-mediated and do not respond to antihistamines, corticosteroids, or epinephrine. Current therapies instead target bradykinin production or replace deficient C1 esterase inhibitor (C1-INH).

C1 Esterase Inhibitor (C1-INH) Replacement

C1-INH replacement restores functional inhibitor levels, suppressing activation of the kallikrein-kinin pathway, and reducing bradykinin production.

C1 esterase inhibitor [human] (Berinert, CSL Behring)

• FDA approval: 2009, with expanded use for self-administration and laryngeal attacks in 2012; approval for all ages in 2016; IV kit in 2021
• Indication: acute abdominal, skin, or laryngeal HAE attacks in adult and pediatric patients
• MOA: plasma-derived C1-INH replacement
• Route of Administration: Intravenous
• Dose: 20 IU/kg administered as soon as possible after symptom onset
• Key efficacy: The IMPACT-1 Phase 3 trial demonstrated significantly faster onset of symptom relief compared with placebo, particularly for abdominal and facial attacks.
• Common adverse effects: Infusion-site reactions, dysgeusia, headache, nausea; thromboembolic events are uncommon.

Recombinant C1 esterase inhibitor (Ruconest, Pharming Healthcare)

• FDA approval: 2014
• Indication: acute HAE attacks in adults and adolescents
• MOA: recombinant C1-INH replacement
• Route of Administration: intravenous
• Dose: 50 IU/kg (maximum 4,200 IU)
• Key efficacy: Phase 3 studies demonstrated more rapid symptom improvement than placebo, with most patients achieving clinically meaningful relief within several hours.
• Common adverse effects: Headache, nausea, diarrhea; contraindicated in patients with known rabbit allergy because of the production system.

Ruconest is the only recombinant human C1-INH currently approved in the US.

Plasma Kallikrein Inhibitors

Ecallantide (Kalbitor, Takeda)

Ecallantide is a recombinant protein that directly inhibits plasma kallikrein.

• FDA approval: 2009
• Indication: treatment of acute HAE attacks in patients ≥12 years
• MOA: Reversible plasma kallikrein inhibitor
• Route of Administration: subcutaneous, as 3 injections
• Dose: 30 mg
• Key efficacy: The Phase 3 EDEMA3 trial and EDEMA4 trial demonstrated significantly greater symptom improvement with ecallantide than placebo.
• Common adverse effects: Headache, nausea, and injection-site reactions
• Safety consideration: Because ecallantide can cause serious hypersensitivity, including anaphylaxis, it must be administered by a healthcare professional with appropriate medical support.

Sebetralstat (Ekterly, KalVista Pharmaceuticals)

Sebetralstat is an oral plasma kallikrein inhibitor.

• FDA approval: 2025
• Indication: acute HAE attacks in adults and pediatric patients ≥12 years (under evaluation for children ≥2 years).
• MOA: oral plasma kallikrein inhibitor
• Route of Administration: oral tablet
• Dose: 600 mg at the earliest recognition of an HAE attack. A second 600-mg dose may be taken after 3 hours if response is inadequate or symptoms worsen or recur; maximum 1,200 mg in 24 hours.
• Key efficacy: The KONFIDENT Phase 3 trial demonstrated significantly faster symptom relief and attack resolution compared with placebo across multiple attack locations. The pivotal trial included 110 treated patients with type I or II HAE.
• Common adverse effects: Headache was the most common adverse reaction in the FDA prescribing information.

As the first FDA-approved oral on-demand therapy for HAE, sebetralstat provides an alternative to injectable or intravenous rescue medications.

Bradykinin B2 Receptor Antagonists

Icatibant (Firazyr, Takeda and multiple generics)

Icatibant directly blocks bradykinin B2 receptors, preventing bradykinin-mediated vascular permeability.

• FDA approval: 2011
• Indication: treatment of acute HAE attacks in adults 18 years of age and older.
• MOA: selective bradykinin B2 receptor antagonist
• Route of Administration: subcutaneous
• Dose: 30 mg; repeat dose in 6 hours to a maximum of 3 doses may be administered if symptoms recur (maximum three doses within 24 hours)
• Key efficacy: The FAST-1, FAST-2, and FAST-3 Phase 3 trials demonstrated significantly faster symptom relief than placebo or tranexamic acid.
• Common adverse effects: Injection-site pain, erythema, swelling, pyrexia, dizziness. Local injection reactions occur in most patients.

Although current on-demand therapies are highly effective, several investigational agents are being investigated for efficacy in simplifying administration or providing faster symptom resolution.

Deucrictibant IR (Pharvaris)

Deucrictibant is an investigational oral bradykinin B2 receptor antagonist being studied for on-demand treatment of HAE attacks.

• FDA Approval: PDUFA is set for April 23, 2027
• Proposed indication: on-demand treatment of HAE attacks
• MOA: oral selective bradykinin B2 receptor antagonist
• Route of Administration: oral soft capsule
• Key efficacy: The Phase 2 RAPIDe-1 study demonstrated rapid symptom improvement with a favorable safety profile.
• Phase 3: The RAPIDe-3 Phase 3 trial (NCT06343779) evaluated oral deucrictibant versus placebo for on-demand treatment of HAE attacks in adolescents and adults. The ClinicalTrials.gov record currently lists the study as completed.
• Common adverse effects: mild GI symptoms and headache have been reported in trials

Mechanistically, deucrictibant resembles icatibant because both block the bradykinin B2 receptor, rather than preventing formation of bradykinin.

How to Select an On-Demand Therapy

Choice of rescue medication depends on clinical and patient-centered factors including:

• age
• prior treatment response
• ability to self-administer therapy
• route of administration preference
• attack location and severity
• availability of medication
• insurance coverage
• patient preference
• adverse effects

Treatment should be initiated as early as possible after symptom onset, as earlier intervention is consistently associated with shorter attacks and improved outcomes.

Patients with laryngeal symptoms should receive immediate on-demand treatment while simultaneously seeking emergency medical evaluation because airway obstruction may progress rapidly.

On-demand treatment remains essential for all patients with HAE, including those receiving effective long-term prophylaxis. Available therapies treat attacks through three principal mechanisms: replacement of deficient C1-INH, inhibition of plasma kallikrein, or blockade of the bradykinin B2 receptor.

Sources

• Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363(6):532-541.
• Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363(6):523-531.
• 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(4):801-808.
• Levy RJ, Lumry WR, McNeil DL, et al. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104(6):523-529.
• Longhurst H, Cicardi M, Craig T, et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med. 2017;376(12):1131-1140.
• Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B₂ receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011;107(6):529-537.
• Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214
• Maurer M, Stobiecki M, Valerieva A, et al. Oral deucrictibant for on-demand treatment of hereditary angioedema attacks (RAPIDe-1): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Haematol. 2026;13(4):e200-e214.
• RAPIDe-3: Study of oral deucrictibant soft capsule for on-demand treatment of angioedema attacks in adolescents and adults with hereditary angioedema (NCT06343779). ClinicalTrials.gov. Phase 3 study. ClinicalTrials.gov
• Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014;112(2):163-169.e1.
• Riedl MA, Farkas H, Aygören-Pürsün E, et al. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks. N Engl J Med. 2024;391(1):32-43. doi:10.1056/NEJMoa2314192.
• C1 esterase inhibitor (human) (Berinert)—prescribing information. US Food and Drug Administration.
• C1 esterase inhibitor (recombinant) (Ruconest)—prescribing information. US Food and Drug Administration.
• Ecallantide (Kalbitor)—prescribing information. US Food and Drug Administration.
• Icatibant (Firazyr)—prescribing information. US Food and Drug Administration.
• Sebetralstat (Ekterly)—prescribing information. US Food and Drug Administration. Initial US approval 2025; prescribing information revised July 2025.