Icatibant
Explore a selection of our essential drug information below, or:
Identification
- Summary
Icatibant is a bradykinin B2 receptor antagonist used to treat acute episodes of swelling and inflammation associated with hereditary angioedema (HAE).
- Brand Names
- Firazyr, Sajazir
- Generic Name
- Icatibant
- DrugBank Accession Number
- DB06196
- Background
Icatibant is a synthetic decapeptide with 5 nonproteinogenic amino acid antagonist targeting the B2 receptors with a similar affinity to bradykinin. It is resistant to bradykinin-cleaving enzyme degradation and has a potency of 2-3 times higher than earlier B2 receptors antagonists, thus representing a new class of medication.1,4 It was investigated as a potential treatment of hereditary angioedema (HAE) as bradykinin was implicated in HAE swelling; specifically, mice lacking B2 receptors showed reduced swelling, thus demonstrating bradykinin involvement in the disease pathophysiology.1,5
Icatibant was approved by the FDA on August 25, 2011, and by the EMA in 2008 as a treatment for hereditary angioedema.8,9 The FDA approval was based on positive results obtained from 3 double-blind, randomized, controlled clinical trials known as FAST 1, 2, and 3, where a median time to almost complete symptom relief was observed to be 8 hours compared to 36 hours for the placebo treatment.8
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Hormones / Peptides - Protein Chemical Formula
- C59H89N19O13S
- Protein Average Weight
- 1304.54 Da
- Sequences
- Not Available
- Synonyms
- Icatibant
- External IDs
- HOE 140
- HOE-140
- HOE140
- Hoechst 140
- JE 049
Pharmacology
- Indication
Icatibant is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Acute attacks of hereditary angioedema •••••••••••• ••••• ••••••••• Treatment of Angioedema caused by ace inhibitors ••• ••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Following bradykinin challenge, intravenous administration of icatibant caused dose and time-dependent inhibition of the development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. Icatibant intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion. Based on exposure-response analysis, a subcutaneous dose of 30 mg icatibant is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown.7
The effect of icatibant 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 90 mg is adequate to represent the high-exposure clinical scenario.7
- Mechanism of action
Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding to the B2 receptor, thereby treating the clinical symptoms of an acute, episodic attack of HAE.7
Target Actions Organism AB2 bradykinin receptor antagonistHumans UAminopeptidase N inhibitorHumans - Absorption
The absolute bioavailability of icatibant following a 30 mg subcutaneous dose is approximately 97%. Maximum plasma concentrations (Cmax) of 974 ± 280 ng/mL were reached when a single subcutaneous dose of 30 mg was administered. The AUC was 2165 ± 568 ng∙hr/mL. Icatibant did not accumulate following multiple doses.7
The pharmacokinetics of icatibant have been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of icatibant in patients with HAE is similar to that in healthy subjects.7
The absolute bioavailability of icatibant following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of icatibant to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng·hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart.7
- Volume of distribution
Following subcutaneous administration, d volume of distribution at steady state (Vss) was 29.0 ± 8.7 L.7
- Protein binding
No information is available on the protein binding of icatibant
- Metabolism
Icatibant is metabolized by proteolytic enzymes into inactive metabolites. The cytochrome P450 enzyme system is not involved with the metabolism of icatibant.7
- Route of elimination
Icatibant's inactive metabolites are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.7
- Half-life
Following subcutaneous administration, mean elimination half-life was 1.4 ± 0.4 hours.7
- Clearance
Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min.7
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Available data from published literature and the pharmacovigilance database with icatibant use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, icatibant, administered by the subcutaneous route during the period of organogenesis, did not cause structural abnormalities in rats or rabbits; however, premature birth and abortion were observed in rabbits at doses approximately 0.025 times the maximum recommended human dose (MRHD) and higher. Decreased embryofetal survival was observed in rabbits at a subcutaneous dose that was 13 times the MRHD. In a pre- and post-natal development study in rats, delayed parturition was observed at subcutaneous doses 0.5 times the MRHD and higher, which resulted in deaths of dams at doses 2 times the MRHD and higher. Fetal death and early pup deaths were observed with doses 2 times the MRHD.7
Two-year studies were conducted in CD1 mice and Wistar rats to assess the carcinogenic potential of icatibant. No evidence of tumorigenicity was observed in mice and rats at icatibant subcutaneous doses up to 15 mg/kg/day (twice per week) and 6 mg/kg/day (daily), respectively (approximately 10-fold and 6-fold greater than the MRHD on an AUC basis, respectively).7
Icatibant tested negative for genotoxicity in the in vitro Ames bacterial reverse mutation test, in vitro Chinese hamster bone marrow chromosome aberration assay, and in vivo mouse micronucleus test.7
Daily subcutaneous administration of icatibant to rats and dogs caused ovarian, uterine, and testicular atrophy/degeneration and adverse effects on the mammary and prostate glands. In rats, testicular atrophy, reduced prostate gland secretion, decreased testosterone levels and degenerate corpora lutea occurred at doses greater than or equal to 3 mg/kg (approximately 5-fold greater than the MRHD in males and 2-fold greater than the MRHD in females on an AUC basis) and a decrease in developing ovarian follicles, mammary gland masculinization, and uterine atrophy occurred at doses greater than or equal to 10 mg/kg (approximately 6-fold greater than MRHD in females on an AUC basis). In dogs, reduced sperm counts and uterine atrophy occurred at doses greater than or equal to 1 mg/kg (approximately 2-fold greater than the MRHD on an AUC basis). Atrophy of the testes and prostate with decreased testosterone levels, decreased ovary size and decreased number of developing follicles occurred at a dose of 10 mg/kg (approximately 30-fold greater than the MRHD in males and 15-fold greater than at the MRHD in females on an AUC basis).7
In contrast to the effects of daily icatibant administration, toxicity to the ovary, uterus, testis, mammary gland, and prostate did not occur in dogs treated twice a week for 9 months. AUC exposures from a dose of 3 mg/kg in these dogs were 5- and 3-fold the MRHD exposures in men and women, respectively. Sperm counts and testosterone remained unaffected over the course of the study in male dogs dosed twice a week.7
Reproduction studies in male mice and rats with daily administration of icatibant found no effects on fertility or reproductive performance with intravenous doses up to 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively.7
In a clinical study evaluating a 90 mg dose (30 mg in each of 3 subcutaneous sites), the adverse event profile was similar to that seen with 30 mg administered in a single subcutaneous site.7
In another clinical study, a dose of 3.2 mg/kg administered intravenously (approximately 8 times the therapeutic dose for HAE) caused erythema, itching, and hypotension in healthy subjects. No therapeutic intervention was necessary.7
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Icatibant which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Icatibant which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Icatibant which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Icatibant which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Icatibant which could result in a lower serum level and potentially a reduction in efficacy. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Icatibant acetate 325O8467XK 138614-30-9 HKMZRZUEADSZDQ-DZJWSCHMSA-N - International/Other Brands
- Firazyr
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Firazyr Solution 10 mg / mL Subcutaneous Takeda Italia S.P.A. 2014-07-14 Not applicable Canada Firazyr Injection, solution 30 mg Subcutaneous Takeda Pharmaceuticals International Ag Ireland Branch 2020-12-16 Not applicable EU Firazyr Injection, solution 30.0 mg/3mL Subcutaneous Takeda Pharma A/S 2011-08-25 Not applicable US Firazyr Injection, solution 30 mg Subcutaneous Takeda Pharmaceuticals International Ag Ireland Branch 2020-12-16 Not applicable EU Icatibant Accord Injection, solution 30 mg Subcutaneous Accord Healthcare, S.L.U. 2021-10-07 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Icatibant Injection, solution 10 mg/1mL Subcutaneous Teva Pharmaceuticals USA, Inc. 2019-07-15 Not applicable US Icatibant Injection, solution 30 mg/3mL Subcutaneous bryant ranch prepack 2021-04-15 Not applicable US Icatibant Injection, solution 30 mg/3mL Subcutaneous Apotex Corporation 2021-04-15 Not applicable US Icatibant Injection 30 mg/3mL Subcutaneous Cipla USA Inc. 2020-07-13 Not applicable US Icatibant Injection, solution 30 mg/3mL Subcutaneous Eugia US LLC 2023-08-14 Not applicable US
Categories
- ATC Codes
- B06AC02 — Icatibant
- Drug Categories
- Agents causing angioedema
- Amino Acids, Peptides, and Proteins
- Analgesics
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Autacoids
- Biological Factors
- Bradykinin B2 Receptor Antagonists
- Bradykinin Receptor Antagonists
- Complement Inactivating Agents
- Drugs that are Mainly Renally Excreted
- Drugs Used in Hereditary Angioedema
- Immunologic Factors
- Inflammation Mediators
- Intercellular Signaling Peptides and Proteins
- Kinins
- Nerve Tissue Proteins
- Neuropeptides
- Oligopeptides
- Peptides
- Peripheral Nervous System Agents
- Proteins
- Sensory System Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 7PG89G35Q7
- CAS number
- 130308-48-4
References
- General References
- Cockcroft JR, Chowienczyk PJ, Brett SE, Bender N, Ritter JM: Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. Br J Clin Pharmacol. 1994 Oct;38(4):317-21. [Article]
- Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W: Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. 2007 Jun;119(6):1497-503. Epub 2007 Apr 5. [Article]
- Bas M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, Veit J, Schossow B, Hapfelmeier A, Kehl V, Kojda G, Hoffmann TK: A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015 Jan 29;372(5):418-25. doi: 10.1056/NEJMoa1312524. [Article]
- Floccard B, Hautin E, Bouillet L, Coppere B, Allaouchiche B: An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II. Core Evid. 2012;7:105-14. doi: 10.2147/CE.S24743. Epub 2012 Sep 27. [Article]
- Campos RA, Valle SO, Franca AT, Cordeiro E, Serpa FS, Mello YF, Malheiros T, Toledo E, Mansour E, Fusaro G, Grumach AS: Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study. Sao Paulo Med J. 2014;132(5):261-5. doi: 10.1590/1516-3180.2014.1325652. Epub 2014 Jul 22. [Article]
- FDA Approved Drug Products: FIRAZYR (icatibant) injection [Link]
- FDA Approved Drug Products:FIRAZYR (icatibant) Injection, for subcutaneous use (Jan 2024) [Link]
- FDA Approves Shire's FIRAZYR® (icatibant injection) for Acute Attacks of Hereditary Angioedema (HAE) [Link]
- Shire Receives European Approval for Label Extension of FIRAZYR® (icatibant injection) for the Symptomatic Treatment of Acute HAE Attacks in Paediatric Patients [Link]
- External Links
- Human Metabolome Database
- HMDB0015624
- KEGG Drug
- D04492
- PubChem Compound
- 71364
- PubChem Substance
- 99443237
- ChemSpider
- 5293384
- BindingDB
- 50403371
- 1148138
- ChEBI
- 68556
- ChEMBL
- CHEMBL2028850
- Therapeutic Targets Database
- DCL000131
- PharmGKB
- PA164749185
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Icatibant
- FDA label
- Download (543 KB)
- MSDS
- Download (87.6 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Hereditary Angioedema (HAE) 1 somestatus stop reason just information to hide Not Available Completed Basic Science Ischemic Heart Disease 2 somestatus stop reason just information to hide Not Available Recruiting Not Available Hereditary Angioedema (HAE) 1 somestatus stop reason just information to hide 4 Completed Treatment Hereditary Angioedema (HAE) 1 somestatus stop reason just information to hide 4 Recruiting Basic Science Heart Failure 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Parenteral; Subcutaneous 30 MG Injection, solution Subcutaneous 30.0 mg/3mL Solution Subcutaneous 10 mg / mL Solution Subcutaneous 30 mg Injection Subcutaneous 30 mg/3mL Injection, solution Subcutaneous 10 mg/1mL Injection, solution Subcutaneous 30 mg/3mL Injection, solution Subcutaneous 30 MG Injection, solution 30 MG/3ML Solution Subcutaneous 30 mg / 3 mL Injection, solution Parenteral 30 mg Injection, solution Parenteral 30 mg/3ml Injection, solution 30 MG - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5648333 No 1997-07-15 2019-07-15 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 1 mg/mL MSDS
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system
- Specific Function
- bradykinin receptor activity
- Gene Name
- BDKRB2
- Uniprot ID
- P30411
- Uniprot Name
- B2 bradykinin receptor
- Molecular Weight
- 44460.15 Da
References
- Privitera PJ, Beckstead RM, Yates P, Walgren R: Autoradiographic localization of [125I-Tyr0]bradykinin binding sites in brains of Wistar-Kyoto and spontaneously hypertensive rats. Cell Mol Neurobiol. 2003 Oct;23(4-5):805-15. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Drug Products:FIRAZYR (icatibant) Injection, for subcutaneous use (Jan 2024) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Broad specificity aminopeptidase which plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Also involved in the processing of various peptides including peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. May also be involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis and promote cholesterol crystallization. May have a role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 and regulating its activity (By similarity)
- Specific Function
- aminopeptidase activity
- Gene Name
- ANPEP
- Uniprot ID
- P15144
- Uniprot Name
- Aminopeptidase N
- Molecular Weight
- 109538.68 Da
References
- Bawolak MT, Fortin JP, Vogel LK, Adam A, Marceau F: The bradykinin B2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: off-target alterations of signaling mediated by the bradykinin B1 and angiotensin receptors. Eur J Pharmacol. 2006 Dec 3;551(1-3):108-11. Epub 2006 Sep 8. [Article]
Drug created at March 19, 2008 16:16 / Updated at August 02, 2024 07:31