Kalbitor

Generic Name: Ecallantide
Class: Complement Inhibitors
Molecular Formula: C₃₀₅H₄₄₂O₉₁S₈
CAS Number: 460738-39-9

• Hypersensitivity


• 
  

  Potential for severe hypersensitivity reactions (e.g., anaphylaxis).¹ (See Sensitivity Reactions under Cautions.)

  
  


• 
  

  Clinicians should be aware of the similarity between symptoms of a hypersensitivity reaction and a hereditary angioedema (HAE) attack; administer only in a setting equipped to monitor and treat hypersensitivity reactions and HAE attacks.¹

  
  


• 
  

  Do not administer to patients with known hypersensitivity to ecallantide.¹

  
  

REMS:

FDA approved a REMS for ecallantide to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of ecallantide and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Selective, reversible plasma kallikrein inhibitor; biosynthetic (recombinant DNA origin) protein.^{1 2 3 4 5 6}

Uses for Kalbitor

Hereditary Angioedema

Treatment of acute angioedema attacks in patients with hereditary angioedema (HAE).^{1 2 5 12 13}

Designated an orphan drug by FDA for this use.⁷

Kalbitor Dosage and Administration

General

• 
  

  Administer only under supervision of qualified clinicians experienced in management of anaphylaxis and HAE and in a setting with appropriate and readily available medical support (e.g., antihistamines, epinephrine, corticosteroids) to manage such conditions.^{1 3 4 8 9 10 15}

  
  


• 
  

  Monitor for possible hypersensitivity reactions (e.g., anaphylaxis) for an appropriate period of time (i.e., at least 1 hour) after administration.^{1 9 10 15}

  
  


• 
  

  If persistent HAE attack symptoms are present, assess patient carefully prior to administration of second dose of ecallantide to determine whether symptoms represent HAE attack or hypersensitivity reaction.^{1 10} (See Sensitivity Reactions under Cautions.)

  
  

REMS Program

• 
  

  FDA has approved REMS program for ecallantide.^{1 5 9}

  
  


• 
  

  The program consists of a medication guide (see Advice to Patients) and a communication plan that targets clinicians who routinely provide care for patients with HAE attacks.^{1 9 10 11}

  
  


• 
  

  Goals of the program are to explain the risks and benefits of ecallantide therapy to patients and to inform clinicians of the risk of anaphylaxis and of the importance of distinguishing between symptoms of an HAE attack and a hypersensitivity reaction.^{1 9 10}

  
  

Administration

Sub-Q Administration

Administer by sub-Q injection.^{1 2 4 12 13}

Vials are for single use only.¹

To prepare a 30-mg dose: Withdraw 1 mL of ecallantide injection from a vial containing 10 mg/mL of the drug into an appropriately sized syringe using a large-bore needle.¹ Perform procedure with each of 3 vials to prepare total dose (3 syringes each containing ecallantide 10 mg). ¹

Prior to administration, replace large-bore needle on each syringe with a 27-gauge needle for sub-Q injection.¹

Observe strict aseptic technique; drug vials contain no preservative.¹

Inject sub-Q into abdomen, thigh, or upper arm.¹ Use same anatomic site for all 3 injections or select different sites; separate injections administered at same site by 2 inches (5 cm) and inject away from site of HAE attack.¹ Rotation of injection sites not necessary.¹

If a second 30 mg-dose is required, may use same anatomic site as for initial dose or select different site.¹

Dosage

Adults

Hereditary Angioedema

Sub-Q

Patients ≥16 years of age: 30 mg.¹ May administer second 30-mg dose within 24 hours after initial dose for persistent HAE attack symptoms.^{1 10 15}

Prescribing Limits

Adults

Hereditary Angioedema

Sub-Q

Patients ≥16 years of age: Maximum 60 mg (i.e., two 30-mg doses) in 24-hour period.¹

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹

Renal Impairment

No specific dosage recommendations.¹

Geriatric Patients

Select dosage with caution; usually initiate therapy at low end of dosage range.¹ (See Geriatric Use under Cautions.)

Cautions for Kalbitor

Contraindications

• 
  

  Known hypersensitivity to ecallantide or any ingredient in formulation.^{1 9}

  
  

Warnings/Precautions

Sensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, hypotension), including anaphylaxis.^{1 2 5 6 15} Monitor patient; such reactions usually occur within first hour following drug administration.^{9 10 15} (See General under Dosage and Administration.)

Because symptoms of hypersensitivity can resemble those of acute HAE attacks, carefully consider treatment method.^{1 9 10 15} Use of medical support for anaphylaxis (e.g., epinephrine, antihistamines, corticosteroids) may be required.^{1 2}

Response to antihistamine and sympathomimetic therapy may distinguish between hypersensitivity reaction (a histamine-mediated event) and acute HAE attack (bradykinin-mediated event); hypersensitivity reactions likely to respond to this type of medical intervention, while HAE attack symptoms likely to be resistant.^{1 2}

Immunogenicity

Development of anti-ecallantide antibodies reported occasionally.^{1 2 15} Neutralizing antibodies to ecallantide also reported, as were IgE antibodies to ecallantide and yeast (Pichia pastoris).^{1 2 15}

Seroconversion rate increases with number of doses received.^{1 5 9 15} Risk of hypersensitivity reactions may be increased in patients with anti-ecallantide antibodies.¹

Long-term effects of antibody formation not known.^{1 5 9 15}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether ecallantide is distributed into milk.¹ Use caution.¹

Pediatric Use

Safety and efficacy not established in children <16 years of age.^{1 5 15}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in the elderly.¹

Hepatic Impairment

Safety and efficacy not established.¹

Renal Impairment

Safety and efficacy not established.¹

Common Adverse Effects

Headache,^{1 2} nausea, ^{1 2} diarrhea, ^{1 2} pyrexia,^{1 2} injection site reactions,^{1 2} nasopharyngitis.^{1 2}

Interactions for Kalbitor

No formal drug interaction studies to date.¹

Kalbitor Pharmacokinetics

Absorption

Bioavailability

Approximately 90%.^{2 4 5 15}

Onset

Peak plasma concentrations attained within 2–3 hours following single 30-mg sub-Q dose.^{1 2 4 5 15}

Distribution

Extent

Not known whether distributed into milk.¹

Elimination

Elimination Route

Excreted in urine; since drug is a small protein, metabolic catabolism (or degradation) also likely.^{2 4 5 15 16}

Half-life

Approximately 2 hours.^{1 2 6}

Special Populations

Pharmacokinetics not studied in patients with hepatic or renal impairment.¹

Stability

Storage

Parenteral

Injection

2–8°C.¹ Protect from light.¹

Vials removed from refrigerator should be stored below 30°C and used within 14 days or returned to refrigeration until use.¹

Actions

• 
  

  Prevents binding of kallikrein to target receptor.^{1 2 3 4 6 8 12 13}

  
  


• 
  

  Inhibits kallikrein activity and prevents conversion of high-molecular weight kininogen to bradykinin.^{1 2 3 4 6 12 13}

  
  


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  Reduced plasma concentrations of bradykinin result in reduction of bradykinin-mediated HAE attack symptoms (e.g., swelling, inflammation, pain).^{1 3 4 12 13}

  
  


• 
  

  Prolongation of thrombin time (>30 seconds) reported rarely; however, no clinically important effects on coagulation parameters (i.e., aPTT, PT) in patients with HAE receiving the drug by sub-Q injection.^{2 5 14} No abnormal patterns or increased risk of bleeding or thrombosis.^{2 5 14 15}

  
  


• 
  

  No clinically important effects on QT_c interval, heart rate, or other ECG measurements.^{2 14 15}

  
  

Advice to Patients

• 
  

  Under the terms fo the REMS approved by FDA for ecallantide, a medication guide must be provided to the patient each time the drug is administered.¹⁰ Importance of discussing potential risks and benefits of therapy with the patient; importance of the patient reading the medication guide prior to initiation of therapy and before subsequent treatment.^{1 11}

  
  


• 
  

  Importance of differentiating serious hypersensitivity reactions to ecallantide from symptoms of an HAE attack.^{1 9 10}

  
  


• 
  

  Risk of hypersensitivity reactions, including anaphylaxis.¹ Importance of immediately informing clinician of possible hypersensitivity symptoms (e.g., shortness of breath, cough, chest tightness, trouble breathing, dizziness, fainting, irregular heartbeat, anxiety, reddening of the face, itching, hives, feeling of warmth, swelling of the throat or tongue, throat tightness, hoarse voice, trouble swallowing, runny nose, sneezing).^{1 10} Inform patients that most reactions occur within 1 hour following sub-Q injection of ecallantide.¹⁰ Importance of not administering ecallantide to patients with a history of hypersensitivity to the drug.^{1 9 10}

  
  


• 
  

  Importance of women informing their clinician 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 and dietary or herbal supplements.¹

  
  


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  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.

Ecallantide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	10 mg/mL	Kalbitor	Dyax

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Dyax. Kalbitor (ecallantide) prescribing information. Cambridge, MA; 2009 Dec.

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

3. 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]

4. 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]

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

6. Christiansen SC, Zuraw BL. Update on therapeutic developments for hereditary angioedema. Allergy Asthma Proc. 2009 Sep-Oct; 30:500-5. [PubMed 19843404]

7. Food and Drug Administration. Orphan designation 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 website). Accessed 2010 May 3.

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

9. Dyax. Important safety information for healthcare professionals. Risk evaluation mitigation strategy (REMS) for Kalbitor (ecallantide) injection. Cambridge, MA Accessed 2010 Apr 23..

10. Dyax. Dear healthcare professional letter regarding important drug warning for Kalbitor (ecallantide) injection. Cambridge MA; Accessed 2010 Apr 23.

11. Dyax. Kalbitor (ecallantide) injection medication guide. Available from manufacturer website. Cambridge, MA; 2009 Dec.

12. Cicardi M, Levy RJ, McNeil DL et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010; 363:523-31. [PubMed 20818887]

13. 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; 104:523-9.

14. Dyax. FDA advisory committee briefing document on Kalbitor (ecallantide) for acute attacks of hereditary angioedema. BLA 125277. 2009 Jan 2. From FDA website.

15. Garnock-Jones KP. Ecallantide in acute hereditary angioedema. Drugs. 2010; 70:1423-31. [PubMed 20614949]

16. Dyax, Cambridge, MA: Personal communication.

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