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Icatibant Acetate

Class: Complement Inhibitors
Chemical Name: d - Arginyl - l - arginyl - l - prolyl - trans - 4 - hydroxy - l - prolylglycyl - 3 - (2 - thienyl) - l - alanyl - l - seryl - d - 1,2,3,4 - tetrahydro - 3 - isoquinolinecarbonyl - l - (2α,3aβ,7aβ) - octahydro - 1H - indole - 2 - carbonyl - l - arginine acetate (salt)
Molecular Formula: C59H89N19O13S.xC2H4O2
CAS Number: 138614-30-9
Brands: Firazyr

Introduction

Synthetic decapeptide similar in structure to bradykinin; a selective bradykinin type 2 (B2) receptor antagonist.1 2 5

Uses for Icatibant Acetate

Hereditary Angioedema

Treatment of acute attacks of hereditary angioedema (HAE);1 2 6 21 designated an orphan drug by FDA for this use.9

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Currently not FDA-labeled or recommended for prophylaxis of HAE attacks.1 13

Icatibant Acetate Dosage and Administration

General

  • Patients may self-administer drug after receiving training from healthcare provider.1

Administration

Sub-Q Administration

Inject sub-Q into abdomen over at least 30 seconds until entire contents of syringe have been expelled; administer about 5–10 cm (2–4 inches) below the umbilicus and ≥5 cm (≥2 inches) from scars.1

Use 25-gauge needle supplied by manufacturer; do not use any other needle.1

Dosage

Available as icatibant acetate; dosage expressed in terms of icatibant.1

Adults

Hereditary Angioedema
Sub-Q

Inject 30 mg at onset of acute attack.1 12 May repeat dose every 6 hours as needed for recurring symptoms or inadequate response, up to maximum of 3 doses (90 mg total) within a 24-hour period.1 12

Prescribing Limits

Adults

Hereditary Angioedema
Sub-Q

Maximum 90 mg in 24-hour period.1 12

Special Populations

Hepatic Impairment

No dosage adjustment required.1

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No dosage adjustment required.1

Cautions for Icatibant Acetate

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

Laryngeal Attacks

Risk of airway obstruction during acute laryngeal HAE attack; immediately seek medical attention in appropriate healthcare facility in addition to treatment with icatibant.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy in patients <18 years of age not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Injection site reactions (e.g., bruising, hematoma, burning, erythema, hypoesthesia, irritation, numbness, edema, pain, pressure sensation, pruritus, swelling, urticaria, warmth),1 2 pyrexia,1 elevated serum aminotransferase concentrations,1 2 dizziness,1 2 rash.1

Interactions for Icatibant Acetate

No formal drug interaction studies to date.1 However, icatibant is not metabolized by CYP isoenzymes.1

Specific Drugs

Drug

Interaction

ACE inhibitors (e.g., captopril)1 10

Potential for decreased hypotensive effect of ACE inhibitor1 10

Icatibant Acetate Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability of approximately 97% when given sub-Q dose.1

Peak plasma concentrations achieved after approximately 0.75 hours after sub-Q dose.1

Special Populations

Hepatorenal syndrome (Clcr 30–60 mL/minute): Plasma concentrations similar to those in patients with normal renal function.1

Geriatric patients (male and female): AUC increased approximately twofold compared with young men and women.1

Patients with low body weight: Increased systemic exposure.1

Female patients (with typically lower body weight than males): AUC and peak plasma concentration increased approximately twofold compared with males.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Elimination

Metabolism

Metabolized extensively by proteolytic enzymes.1

Elimination Route

Excreted principally in urine as inactive metabolites.1

Half-life

Approximately 1.4 hours.1

Special Populations

Mild to moderate hepatic impairment (Child-Pugh score 5–8): Following continuous IV infusion, pharmacokinetic parameters similar to those in healthy individuals.1

Hepatic impairment (Child-Pugh score 7–15): Clearance similar to that in healthy individuals.1

Geriatric patients: Reduced clearance, resulting in increased systemic exposure.1

Patients with low body weight: Reduced clearance, resulting in increased systemic exposure.1

Stability

Storage

Parenteral

Injection

2–25°C.1 Do not freeze.1 Protect from light.12

Actions

  • A synthetic decapeptide similar in structure to bradykinin; a selective bradykinin type 2 (B2) receptor antagonist.1 2 5

  • HAE is a rare autosomal-dominant genetic disorder characterized by a mutation in the complement 1 (C1)-inhibitor gene;1 8 14 15 16 17 18 21 deficiency in C1-esterase inhibitor results in unrestrained activity of plasma kallikrein and elevated bradykinin levels, which leads to increased vascular permeability and angioedema.1 4 5 8 12 14 15 16 17 18 19 20

  • Competitive inhibition of the bradykinin B2 receptor reduces the vasodilatory effects of excess bradykinin.1 4 5 7 8

Advice to Patients

  • Advise patients of maximum dosage; do not administer >3 doses of 30 mg each (total of 90 mg) within a 24-hour period.1

  • Advise patients to immediately seek medical attention after treating a laryngeal HAE attack with icatibant.1

  • Risk of injection site reactions.1 Importance of patients informing clinicians if any erythema, bruising, swelling, warmth, burning sensation, pruritus, irritation, urticaria, numbness, pressure, or pain occurs at injection site.1

  • Risk of pyrexia, elevated serum aminotransferases (ALT, AST), and rash.1

  • Risk of fatigue, drowsiness, and dizziness; do not perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) if such symptoms occur.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Icatibant Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

10 mg (of icatibant) per mL (30 mg)

Firazyr (available as disposable prefilled syringes)

Shire

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Shire. Firazyr (icatibant acetate) injection prescribing information. Lexington, MA; 2011 Aug.

2. Cicardi M, Banerji A, Bracho F et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010; 363:532-41. [PubMed 20818888]

3. Shire, Wayne, PA: Personal communication.

4. Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg. 2010; 110:1271-80. [PubMed 20418292]

5. Bernstein JA. Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies. Ann Allergy Asthma Immunol. 2008; 100(1 Suppl 2):S41-6.

6. 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 Dec; 107(6):529-37.

7. Bouillet L. Icatibant in hereditary angioedema: news and challenges. Expert Rev Clin Immunol. 2011; 7:267-72. [PubMed 21595592]

8. Longhurst HJ. Management of acute attacks of hereditary angioedema: potential role of icatibant. Vasc Health Risk Manag. 2010; 6:795-802. [PubMed 20859548]

9. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site

10. Gainer JV, Morrow JD, Loveland A et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998; 339:1285-92. [PubMed 9791144]

11. Wagner F, Rosenkranz B, Knolle J. Absolute bioavailability of subcutaneously administered icatibant, a selective and potent bradykinin B2 receptor antagonist . J Allergy Clin Immunol. 2007;119:S274. (Abstract No. 1071.)

12. Shire. FDA advisory committee briefing document on Firazyr (icatibant acetate) for the treatment of acute attacks of hereditary angioedema (HAE) in patients 18 years of age and older. NDA 022-150. 2011 Jun 23. From FDA website.

13. Longhurst HJ, Farkas H, Craig T et al. HAE international home therapy consensus document. Allergy Asthma Clin Immunol. 2010; 6:22. [PubMed 20667125]

14. Bernstein JA, Qazi M. Ecallantide: its pharmacology, pharmacokinetics, clinical efficacy and tolerability. Expert Rev Clin Immunol. 2010; 6:29-39. [PubMed 20383888]

15. Schneider L, Lumry W, Vegh A et al. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol. 2007; 120:416-22. [PubMed 17559913]

16. Lehmann A. Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther. 2008; 8:1187-99. [PubMed 18613770]

17. Center for Drug Evaluation and Research, Food and Drug Administration. Application number 125277 summary review. From FDA website.

18. Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008; 68:2561-73. [PubMed 19093699]

19. Schneider L, Lumry W, Vegh A et al. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol. 2007; 120:416-22. [PubMed 17559913]

20. Lehmann A. Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther. 2008; 8:1187-99. [PubMed 18613770]

21. Bowen T, Cicardi M, Farkas H et al. 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allerg Asthma Clin Immunol. 2010; 6(1):24.

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