Icatibant

A synthetic decapeptide bradykinin B2 receptor antagonist, FDA approved since 2011 (generics since 2019) as a self-administered subcutaneous injection for acute attacks of hereditary angioedema in adults, that failed in ACE-inhibitor angioedema and COVID-19 trials.

Also referenced as: Icatibant acetate, HOE 140, HOE-140, Hoe140, JE049, Firazyr, Sajazir

Also appears in: Cardiovascular

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What is Icatibant?

Icatibant is a synthetic decapeptide that acts as a selective, competitive antagonist of the bradykinin B2 receptor. Its sequence (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg) is built on the bradykinin backbone but contains five non-proteinogenic residues, including D-amino acids and the constrained residues D-Tic and Oic, which make it resistant to the peptidases that clear bradykinin in seconds and give it a mean plasma elimination half-life of about 1.4 hours after subcutaneous injection. It was developed at Hoechst under the code HOE 140 in the late 1980s, brought through clinical trials by Jerini as JE049, and is supplied clinically as the acetate salt.

It is approved in the United States as Firazyr (NDA 022150, August 25, 2011) and as several generic and branded-generic icatibant injections, for the treatment of acute attacks of hereditary angioedema (HAE) in adults. In the research market it is sold under the name icatibant or HOE 140 as a reference B2 receptor antagonist, the standard pharmacological tool for testing whether a response in a cell or tissue preparation depends on bradykinin signaling.

How it works

Hereditary angioedema attacks are driven by unregulated plasma kallikrein activity and excess bradykinin, not by histamine, which is why antihistamines and corticosteroids do not work and why a bradykinin receptor blocker does. Icatibant acts at the final step of that cascade:

• Potent, long-acting B2 receptor antagonism — HOE 140 displaced bradykinin from B2 binding sites in guinea-pig ileum with an IC50 near 1 nM and blocked bradykinin-induced release of endothelium-derived relaxing factor and calcium mobilization in cultured bovine endothelial cells, two to three orders of magnitude more potently than the earlier reference antagonist (Hock et al., British Journal of Pharmacology, 1991, 102(3):769–773)
• Durable in vivo blockade — in the companion study, a single subcutaneous dose still suppressed bradykinin-induced hypotension in rats by 60% four hours later, strongly inhibited bradykinin-induced bronchoconstriction in guinea pigs, and reduced carrageenan paw edema, which established the long duration of action that distinguishes it from the first-generation peptide antagonists (Wirth et al., British Journal of Pharmacology, 1991, 102(3):774–777)
• The target is the mediator actually elevated during attacks — using extraction, HPLC and radioimmunoassay, plasma bradykinin was shown to rise two- to twelve-fold above the upper limit of normal during acute attacks of hereditary and acquired angioedema and to fall immediately after C1-inhibitor infusion, providing the direct human evidence that bradykinin is the swelling mediator a B2 antagonist should block (Nussberger et al., Lancet, 1998, 351(9117):1693–1697)
• Receptor-level, not cascade-level, intervention — unlike C1-inhibitor concentrates (which replace the missing regulator) or plasma kallikrein inhibitors (which stop bradykinin production), icatibant leaves bradykinin generation untouched and blocks its vascular effect, which is why its action is rapid but time-limited and why redosing is sometimes needed within an attack (Cicardi et al., New England Journal of Medicine, 2010, 363(6):532–541)

Research status

Icatibant has a completed Phase 3 program in hereditary angioedema, approvals in the U.S., EU, Japan and elsewhere, more than a decade of registry data, and a string of negative trials outside its approved indication.

FAST-1 (NCT00097695) and FAST-2 (NCT00500656). The two pivotal “For Angioedema Subcutaneous Treatment” trials, published together, randomized 56 patients (FAST-1, placebo-controlled) and 74 patients (FAST-2, against oral tranexamic acid) with cutaneous or abdominal HAE attacks to a single 30 mg subcutaneous injection. In FAST-1 the median time to clinically significant relief was 2.5 hours with icatibant versus 4.6 hours with placebo, a difference that was not statistically significant (P = 0.14), with the authors attributing part of the shortfall to early rescue medication in the placebo arm (3 icatibant versus 13 placebo recipients). In FAST-2 the median was 2.0 hours versus 12.0 hours with tranexamic acid (P < 0.001). No icatibant-related serious adverse events were reported (Cicardi et al., New England Journal of Medicine, 2010, 363(6):532–541). The FAST-1 miss contributed to the FDA’s 2008 not-approvable letter; the European Commission approved the drug on July 11, 2008 on the same data.

FAST-3 (NCT00912093). The confirmatory Phase 3 trial randomized 98 patients; in the cutaneous and abdominal cohort (43 icatibant, 45 placebo) the median time to at least a 50% reduction in a composite visual-analog symptom score was 2.0 hours versus 19.8 hours with placebo (P < .001), with similar adverse event rates between arms. A small laryngeal cohort (3 icatibant, 2 placebo) was analyzed descriptively only (Lumry et al., Annals of Allergy, Asthma & Immunology, 2011, 107(6):529–537). This trial is the “Trial 1” in the U.S. label and supplied the data for the August 2011 approval, including self-administration after training.

Pediatric program. A Phase 3 single-dose study (HGT-FIR-086, NCT01386658) treated 32 patients aged 2 to under 18 with 0.4 mg/kg (maximum 30 mg); among the 22 with an attack, the median time to onset of symptom relief was 1.0 hour in both children and adolescents, and injection-site reactions occurred in 90.6% of patients (Farkas et al., Journal of Allergy and Clinical Immunology: In Practice, 2017, 5(6):1671–1678.e2). On this study the CHMP adopted a positive opinion on September 14, 2017 extending the EU indication to adults, adolescents and children aged 2 years and older, with weight-banded doses from 10 mg (12–25 kg) to 30 mg (over 65 kg). The U.S. label has not been extended: as of the June 2025 revision it remains limited to adults 18 years and older and states that pediatric safety and effectiveness have not been established.

Real-world safety. The Icatibant Outcome Survey, an industry-sponsored observational registry started in 2009 (NCT01034969), analyzed 3,025 icatibant-treated attacks in 557 patients enrolled from 2009 to 2015; 43 adverse events in 17 patients (3.1%) were judged drug-related, and no icatibant-related serious adverse events occurred in patients with cardiovascular disease or in those dosing more often than the label (Zanichelli et al., Allergy, 2017, 72(6):994–998). A ten-year review of the same registry (549 patients and 5,995 attacks as of March 2019) concluded that real-world effectiveness matched the trial results, that one dose resolved most attacks, and that earlier self-administration shortened attacks (Maurer et al., Clinical & Experimental Allergy, 2022, 52(9):1048–1058).

ACE-inhibitor angioedema — a failure after a promising start. A small German Phase 2 trial (27 patients in the per-protocol analysis) reported median time to complete resolution of 8.0 hours with icatibant versus 27.1 hours with intravenous prednisolone plus clemastine (P = 0.002) (Baş et al., New England Journal of Medicine, 2015, 372(5):418–425). The larger confirmatory trial randomized 121 adults presenting within 12 hours of at least moderately severe ACE-inhibitor-induced upper airway angioedema to icatibant 30 mg or placebo and found no difference in time to meeting discharge criteria (median 4.0 hours in both arms, P = .63) or in time to symptom relief (Sinert et al., Journal of Allergy and Clinical Immunology: In Practice, 2017, 5(5):1402–1409.e3). Icatibant has no approval for this use, and the negative Phase 3 is the better-powered study.

COVID-19 — not effective. Interest began with a nine-patient case-control report in which oxygen requirements fell after icatibant (van de Veerdonk et al., JAMA Network Open, 2020, 3(8):e2017708). The open-label Phase 2 ICAT-COVID trial (NCT04978051) randomized 73 hospitalized patients to three days of 30 mg three times daily plus standard care or standard care alone; the primary endpoint, clinical response on day 10, was 73.0% versus 55.6% and not significant (P = .115), with a secondary mortality difference (0 versus 6 deaths) that rested on few events (Malchair et al., Clinical Infectious Diseases, 2023, 76(10):1784–1792). In the I-SPY COVID adaptive platform trial in critically ill patients, the icatibant arm (n = 96) did not meet the prespecified criterion for a large effect on time to recovery or mortality and was closed (I-SPY COVID Consortium, EClinicalMedicine, 2023, 58:101889).

Other and ongoing work. ClinicalTrials.gov lists one active icatibant-specific interventional study as of November 2026: a Vanderbilt University Medical Center randomized, double-blind, placebo-controlled crossover study of intravenous icatibant infusion (100 µg/kg/h for 15 minutes before dialysis, then 50 µg/kg/h during the session, at 12 sessions over four weeks) to prevent intradialytic hypotension in hemodialysis patients (NCT05834777, registered as Phase 3 but described by the sponsor as explorative, 26 participants, active and not recruiting, primary completion November 2026). The I-SPY COVID platform record (NCT04488081) also remains listed as active, but its icatibant arm closed in 2021. No new U.S. indication was approved in 2025 or 2026; the June 2025 label revision did not change the indication, and U.S. activity since 2019 has consisted of abbreviated new drug application approvals for generic icatibant injections, beginning with Teva’s in July 2019, including Cipla’s 2020 ANDA under which Cycle Pharmaceuticals markets the branded generic Sajazir.

Common dosage forms

• Single-dose prefilled syringe (approved product and generics) — 30 mg of icatibant (as 11.38 mg/mL icatibant acetate, equivalent to 10 mg/mL free base) in 3 mL of preservative-free aqueous solution, packaged with a 25-gauge needle for subcutaneous injection into the abdomen. Cartons of one or three syringes; stored at 2–25 °C, never frozen. The product is designed for self-administration or caregiver administration after training.
• Weight-based pediatric volumes abroad — in the EU the same 30 mg/3 mL syringe is used, with the volume graduated by weight band, for children aged 2 years and older; there is no separate pediatric strength.
• Intravenous infusion — used only in investigational settings (the ongoing hemodialysis study); no intravenous icatibant product is marketed.
• Research supply — icatibant acetate as lyophilized powder, usually labeled HOE 140, in milligram vials for reconstitution as a laboratory B2 receptor antagonist.

Key considerations

• The approval is narrow and the molecule has no proven use outside it. FDA Approved status reflects that approved products containing icatibant exist for acute HAE attacks in adults. Prophylaxis of HAE, pediatric use in the U.S., ACE-inhibitor angioedema, and COVID-19 are either unapproved or have failed in controlled trials; the two best-powered off-indication studies (Sinert 2017; the I-SPY COVID arm) were negative.
• Laryngeal attacks still require emergency care. The label warns that patients treated for a laryngeal attack should seek immediate medical attention because of the risk of airway obstruction; the drug relieves swelling but does not secure an airway, and the laryngeal cohorts in the trials were too small for statistical conclusions.
• Injection-site reactions are near-universal and the systemic signal is small. In the placebo-controlled trials 97% of icatibant recipients (75 of 77) versus 33% of placebo recipients had injection-site reactions (erythema, swelling, pain, itching); pyrexia and transaminase elevation (4% each) and dizziness (3%) were the next most common. A theoretical concern that blocking bradykinin could blunt its cardioprotective effects during ischemia (reduced coronary flow in isolated guinea-pig hearts; higher mortality in a dog infarction model) appears in the label’s animal-toxicology section, not among its warnings, with advice to use the drug during acute coronary ischemia or unstable angina only when the benefit exceeds that theoretical risk; registry data in patients with cardiovascular disease have not shown related serious events.
• Mechanism-first, not cascade-first. Icatibant blocks the receptor rather than reducing bradykinin production, so its effect is fast but wears off while an attack may still be generating bradykinin; the label allows repeat dosing within an attack for that reason. This also means it is a different class from C1-inhibitor concentrates and from plasma kallikrein inhibitors, and the three are not interchangeable descriptions of the same approach.
• Naming. HOE 140, Hoe140, JE049, icatibant acetate, Firazyr, and Sajazir all refer to the same decapeptide. Research-vendor listings labeled “bradykinin antagonist” or “B2 antagonist” may instead be older peptide antagonists (for example, D-Arg-[Hyp3,Thi5,8,D-Phe7]-bradykinin) with far lower potency and duration; the sequence, not the pharmacological class, identifies icatibant.