ATryn

Generic Name: Antithrombin alfa
Class: Anticoagulants, Miscellaneous
Chemical Name: Antithrombin (human reduced), human antithrombin-III (ATIII)
Molecular Formula: C2191H3451N583O656S18
CAS Number: 84720-88-7

Introduction

Biosynthetic (recombinant DNA origin) preparation of human antithrombin III, a naturally occurring anticoagulant.1 3 4 5 9

Uses for ATryn

Congenital Antithrombin III Deficiency

Prevention of perioperative and peripartum thromboembolism in patients with congenital antithrombin III deficiency; designated an orphan drug by FDA for use in these conditions.1 2 5

Short-term thromboprophylaxis with an appropriate anticoagulant recommended in patients with congenital antithrombin III deficiency during high-risk situations (e.g., surgery, pregnancy, postpartum period);4 7 8 11 13 antithrombin III concentrates may be used when anticoagulant therapy is neither feasible (e.g., due to a bleeding risk) nor sufficient.1 3 4 5 7 11 12

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Not indicated for treatment of thromboembolic events.1

Heparin Resistance

Has been used for management of heparin resistance during cardiopulmonary bypass (CPB).14 15 16

May reduce requirements for fresh frozen plasma and additional heparin during CPB.15 16

ATryn Dosage and Administration

Administration

IV Administration

Administer by IV infusion using 0.22-mcm inline filter.1 5

Reconstitution

Allow vials of antithrombin alfa (antithrombin [recombinant]) powder for injection to reach room temperature (20–25°C) ≤3 hours prior to reconstitution.1

Reconstitute vial containing approximately 1750 units of drug with 10 mL sterile water for injection immediately before use; do not shake.1 May be further diluted (e.g., to obtain a concentration of 100 units/mL) for IV administration.1 Withdraw reconstituted contents of 1 or more vials (depending on calculated dose) into a sterile disposable syringe or add to an infusion bag containing 0.9% sodium chloride injection.1

Administer as soon as possible or within 8–12 hours of preparation.1 May be stored at room temperature until administration.1 Discard any unused portions.1

Rate of Administration

Administer initial IV loading dose over 15 minutes followed by a continuous IV maintenance infusion.1

Dosage

Potency expressed in international units (IU, units) as tested against activity of the WHO reference standard.1 Each vial contains approximately 1750 units.1

Use different dosing formulas for treatment of pregnant versus nonpregnant patients.1 5 6 (See Distribution: Special Populations, under Pharmacokinetics and see Elimination: Special Populations, under Pharmacokinetics.)

Adults

Congenital Antithrombin III Deficiency
Pregnant Women
IV

Pregnant women undergoing a surgical procedure should be treated according to the dosing formula for pregnant patients.10 Initiate treatment prior to delivery or approximately 24 hours before surgery; continue until adequate follow-on anticoagulation is established.1 5

Loading dose (units) = [ (100 - baseline antithrombin III activity level) / 1.3] × body weight in kg

Maintenance dose (units/hr) = [ (100 - baseline antithrombin III activity level) / 5.4] × body weight in kg

Adjust dosage based on serial monitoring of serum antithrombin III activity levels (expressed as a percentage of normal).1 5 Monitor serum antithrombin III activity levels prior to initiation of therapy and at regular intervals (i.e., once or twice daily) during therapy to achieve therapeutic antithrombin III activity levels in the range of 80–120% of normal.1 5 10

Nonpregnant Surgical Patients
IV

Initiate treatment approximately 24 hours before surgery; continue until adequate follow-on anticoagulation is established.1 5

Loading dose (units) = [ (100 - baseline antithrombin III activity level) / 2.3] × body weight in kg

Maintenance dose (units/hr) = [ (100 - baseline antithrombin III activity level) / 10.2] × body weight in kg

Adjust dosage based on serial monitoring of serum antithrombin III activity levels (expressed as a percentage of normal).1 5 Monitor serum antithrombin III activity levels prior to initiation of therapy and at regular intervals (i.e., once or twice daily) during therapy to achieve therapeutic antithrombin III activity levels in the range of 80–120% of normal.1 5 10

Dosage Adjustments

Adjust dosage based on serum antithrombin III activity levels.1 Obtain measurement of antithrombin III activity 2 hours following initiation of therapy.1 If measured activity level is <80%, increase infusion rate by 30%; if measured activity level is >120%, decrease infusion rate by 30%.1 Recheck serum antithrombin III activity level 2 hours after each dosage adjustment.1 10

If initial measurement of antithrombin III activity after starting therapy is within target range of 80–120%, maintain same dosage and recheck activity level in 6 hours.1 10 Perform subsequent antithrombin III activity level measurements 2 hours after each dosage adjustment or 6 hours after each measurement that falls within the target range of 80–120%.1 10

Obtain serum antithrombin III activity level immediately following surgery or delivery.1 If measured level <80%, may administer an additional loading dose using same formula for initial loading dose (substituting last available serum antithrombin III activity level for baseline value); resume maintenance infusion at previously administered rate.1

Cautions for ATryn

Contraindications

  • Known hypersensitivity to goat and goat milk proteins.1

Warnings/Precautions

Warnings

Concomitant Anticoagulant Therapy

Potential for enhanced anticoagulant effects if used concomitantly with unfractionated heparin, low molecular weight heparin, or other drugs that use antithrombin III to exert their anticoagulant effects.1 (See Interactions.)

Perform coagulation tests (e.g., aPTT, anti-factor Xa activity) at regular and frequent intervals in patients receiving concomitant anticoagulant therapy, especially in the first few hours following initiation or withdrawal of antithrombin alfa (antithrombin [recombinant]) therapy.1 Closely monitor for bleeding or thrombosis.1

Sensitivity Reactions

Hypersensitivity Reactions

Potential for allergic-type hypersensitivity reactions, including anaphylaxis.1 Closely monitor for manifestations of hypersensitivity (e.g., hives, generalized urticaria, chest tightness, wheezing, hypotension, anaphylaxis).1 Immediately discontinue drug and administer appropriate emergency treatment if hypersensitivity occurs.1

Immunogenicity

Potential for antibody development to antithrombin alfa, goat antithrombin, or goat-milk proteins.1 6 11 Confirmed immunologic reactions not reported to date.1 3 4 5 6 10 11

A patient registry has been established to further evaluate immunogenic potential of antithrombin alfa.1 Clinicians encouraged to participate by calling Lundbeck Inc. at 800-455-1141.1

Specific Populations

Pregnancy

Category C.1

Does not appear to be associated with an increased risk of fetal abnormalities when administered during the third trimester.1 5 However, use during pregnancy only if clearly indicated.1

Lactation

Distributed into milk in low concentrations.1 Use with caution and only if clearly indicated.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1 10

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger patients.1 Select dosage with caution, initiating at low end of dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.1

Common Adverse Effects

Hemorrhage,1 infusion site reactions.1

Interactions for ATryn

Specific Drugs

Drug

Interaction

Comments

Anticoagulants (e.g., unfractionated heparin, low molecular weight heparin, other drugs that use antithrombin III to exert their anticoagulant effects)

Possible increased anticoagulant effect1

Half-life of antithrombin alfa may be altered due to change in antithrombin turnover1

Closely monitor patients1 (see Concomitant Anticoagulant Therapy under Cautions)

ATryn Pharmacokinetics

Distribution

Special Populations

Higher volume of distribution in pregnant versus nonpregnant patients.1 5

Elimination

Elimination Route

Irreversible complexes formed between antithrombin III and its target protease are rapidly removed by the liver.1 4 7 11

Half-life

Mean half-life following a single IV dose of 50 or 100 units/kg in patients with congenital antithrombin III deficiency is 11.6 or 17.7 hours, respectively.1

Shorter elimination half-life and more rapid clearance compared with plasma-derived antithrombin III.1 5 6 11

Special Populations

Increased clearance in pregnant women compared with nonpregnant patients.1 5

Stability

Storage

Parenteral

Injection

2–8°C.1

Store reconstituted solutions at room temperature (20–25°C);1 use within 8–12 hours of reconstitution.1

Actions

  • Biosynthetic (recombinant DNA origin) preparation of human antithrombin III produced in milk of transgenic goats.1 3 4 5 9 Involves insertion of DNA coding sequence for human antithrombin III into specific promotor gene that directs expression in goat mammary glands.1 3 4 9 Isolated and purified using a series of filtration and chromatography steps; includes additional viral inactivation procedures.1 3 4 6

  • Regulates several key serine proteases in the blood coagulation pathway.1 3 4 7 9 11 Principally inhibits thrombin and factor Xa, and to a lesser extent, factors IXa, XIa, XIIa, trypsin, plasmin, tissue plasminogen activator (tPA), urokinase, and kallikrein.1 3 4 7 9 11 Activity enhanced by more than 300- to 1000-fold when antithrombin III is bound to heparin.1 3 4 7 9 10 11

  • Functionally and structurally similar to endogenous antithrombin III.1 3 4 5 9

  • Also exhibits anti-inflammatory and antiproliferative effects in endothelium.4 11

Advice to Patients

  • Risk of allergic-type hypersensitivity reactions; importance of recognizing early manifestations of hypersensitivity (e.g., hives, generalized urticaria, chest tightness, wheezing, hypotension, anaphylaxis) and immediately informing a clinician if any of these signs or symptoms occur.1

  • Importance of reporting any previous or current known hypersensitivity to goat or goat milk proteins prior to receiving antithrombin alfa.1

  • Risk of bleeding with concurrent use of antithrombin alfa and other anticoagulants; importance of informing a clinician if any bleeding occurs during treatment.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.

Antithrombin Alfa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

number of units indicated on vial

ATryn

GTC Biotherapeutics, (marketed by Lundbeck)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2010. 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. GTC Biotherapeutics, Inc. ATryn (antithrombin recombinant) lyophilized powder for reconstitution prescribing information. Framingham, MA; 2009 Feb.

2. 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. Accessed 2009 Feb 20.

3. Konkle BA, Bauer KA, Weinstein R et al. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion. 2003; 43:390-4. [PubMed 12675726]

4. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008; 14:1229-39. [PubMed 19141163]

5. Tiede A, Tait RC, Shaffer DW et al. Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost. 2008; 99:616-22. [PubMed 18327412]

6. US Food and Drug Administration. Briefing document from the blood products advisory committee. Jan 9, 2009. From FDA website (http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4410B1-5.htm).

7. Cavenagh JD, Colvin BT. Guidelines for the management of thrombophilia. Department of Haematology, The Royal London Hospital, Whitechapel, London, UK. Postgrad Med J. 1996; 72:87-94. [PubMed 8871458]

8. Bates SM, Greer I, Pabinger I et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2008; 133(Suppl):844S-86S. [PubMed 18574280]

9. Edmunds T, Van Patten SM, Pollock J et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood. 1998; 91:4561-71. [PubMed 9616152]

10. Lundbeck Inc: Personal communication.

11. Maclean PS, Tait RC. Hereditary and acquired antithrombin III deficiency: epidemiology, pathogenesis and treatment options. Drugs. 2007; 67:1429-40. [PubMed 17600391]

12. The National Alliance for Thrombosis and Thrombophilia. Antithrombin deficiency: an in-depth guide for patients and health care providers brochure. Chapel Hill, NC; 2006 June.

13. Bauer KA. Management of patients with hereditary defects predisposing to thrombosis including pregnant women. Thromb Haemost. 1995; 74:94-100. [PubMed 8578533]

14. Levy JH, Despotis GJ, Szlam F et al. Recombinant human transgenic antithrombin in cardiac surgery: a dose-finding study. Anesthesiology. 2002; 96:1095-102. [PubMed 11981148]

15. Avidan MS, Levy JH, van Aken H et al. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005; 130:107-13. [PubMed 15999048]

16. Avidan MS, Levy JH, Scholz J et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology. 2005; 102:276-84. [PubMed 15681940]

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