Factor XIII (Human)

Class: Hemostatics
VA Class: BL500
Chemical Name: Human Factor XIII [A2] homodimer (allele F13A*1B)
Molecular Formula: C3708H5735N1013O1111S28
Brands: Corifact

Introduction

Heat-treated, lyophilized coagulation factor XIII concentrate made from pooled human plasma.1 7 8

Uses for Factor XIII (Human)

Congenital Factor XIII Deficiency

Routine prophylaxis of bleeding in patients with congenital factor XIII deficiency;1 7 8 13 14 15 designated an orphan drug by FDA for this use.12

Congenital factor XIII deficiency is a rare bleeding disorder manifested by umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding, poor wound healing, recurrent miscarriage, and life-threatening intracranial hemorrhage.7 9 10 13 14 16 20 23 24 27

Slideshow: 10 Common Symptoms That Should Never Be Ignored

Controlled trials demonstrating a direct benefit of treatment of bleeding episodes with factor XIII (human) in patients with congenital factor XIII deficiency are lacking.1 However, successful prophylaxis or treatment of bleeding using human plasma-derived factor XIII concentrate reported in such patients, principally outside the US (e.g., Europe).7 8 9 13 14 15 16 20 23 24 26

Postmarketing study currently ongoing to evaluate clinical benefit of routine prophylaxis with factor XIII (human) for prevention of spontaneous bleeding in patients with congenital factor XIII deficiency.1

Acquired Factor XIII Deficiency

Has been used to treat acquired factor XIII deficiency associated with various diseases or other conditions.2 3 5 9 17 18 19 21 22 25

Factor XIII (Human) Dosage and Administration

General

  • Monitor factor XIII activity during treatment to individualize dosage.1 (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection only.1 Do not mix with other drug solutions; administer via a separate infusion line.1

Reconstitution

Vials of factor XIII (human) for single use only; contain no preservatives.1

Prior to reconstitution, allow drug and diluent to warm to room temperature.1 Reconstitute lyophilized factor XIII (human) with diluent (sterile water for injection) according to manufacturer's directions.1

Do not refrigerate or freeze reconstituted factor XIII solution.1

Use reconstituted solution promptly, or no more than 4 hours after reconstitution.1 Discard unused portion.1

Rate of Administration

Maximum 4 mL/minute.1

Dosage

Dosage expressed in international units (IU, units) of factor XIII activity.1 Each vial contains 1000–1600 units of factor XIII (human); number of units indicated on each vial and carton.1

Individualize dosage based on body weight, laboratory values, and patient's clinical condition.1

After initial dose, administer every 28 days (every 4 weeks) to maintain trough factor XIII activity level of approximately 5–20%.1

Adjust dose in increments of ±5 units/kg based on trough factor XIII activity levels of <5% or >20% and patient’s clinical condition.1

Pediatric Patients

Congenital Factor XIII Deficiency
IV

Initial dose: 40 units/kg.1

Subsequent dosage: Adjust according to most recent trough factor XIII activity level using specific assay.1 (See Table 1.)

Table 1. Dosage Adjustment Using the Berichrom Activity Assay

Trough Factor XIII Activity

Dosage Change

One trough level of <5%

Increase by 5 units/kg

Trough level of 5–20%

No change

Two trough levels of >20%

Decrease by 5 units/kg

One trough level of >25%

Decrease by 5 units/kg

Adults

Congenital Factor XIII Deficiency
IV

Initial dose: 40 units/kg.1

Subsequent dosage: Adjust according to most recent trough factor XIII activity level using specific assay.1 (See Table 2.)

Table 2. Dosage Adjustment Using the Berichrom Activity Assay

Trough Factor XIII Activity

Dosage Change

One trough level of <5%

Increase by 5 units/kg

Trough level of 5–20%

No change

Two trough levels of >20%

Decrease by 5 units/kg

One trough level of >25%

Decrease by 5 units/kg

Special Populations

Pregnant Women

Achievement of plasma factor XIII activity levels of at least 2–3% (ideally >10%) during early gestation and >30% during labor suggested.8 9 Timing and optimum dosage for maintenance of successful pregnancy not fully elucidated.8

Cautions for Factor XIII (Human)

Contraindications

  • Known anaphylactic or severe systemic reactions to human plasma-derived products or any component in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., allergy, rash, pruritus, erythema) observed.1

Discontinue administration immediately and institute appropriate treatment if manifestations of anaphylaxis or hypersensitivity reactions (e.g., urticaria, rash, tightness of the chest, wheezing, hypotension) occur.1

Factor XIII (human) packaging components do not contain natural rubber latex.1

Immunogenicity

Inhibitory antibodies against factor XIII detected in patients receiving factor XIII (human).1 2 Presence of inhibitory antibodies also may manifest as inadequate response to treatment.1 2

Monitor patients for possible development of inhibitory antibodies.1 If expected plasma factor XIII activity levels not attained or breakthrough bleeding occurs during prophylaxis, measure factor XIII inhibitory antibody concentrations.1

Thromboembolic Complications

Thromboembolic complications reported during postmarketing experience.1

Carefully assess benefits and risks in pregnant women because of their hypercoagulable state and potential for increased risk of thromboembolic events.1

Transmission of Infectious Agents

Factor XIII (human) made from human blood and may carry risk of transmitting infectious agents (e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent).1 Possibility that unknown infectious agents exist in such products.1

Risk of virus transmission reduced by screening plasma donors for prior exposure to certain viruses, testing for presence of certain current virus infections, and by inactivating and removing certain viruses during manufacture.1 Despite these measures, such products may still potentially transmit disease.1

Consider appropriate vaccination (against hepatitis A and B virus) for patients regularly receiving factor XIII (human).1

Report all infections that clinician suspects may have been possibly transmitted by factor XIII (human) to CSL Behring Pharmacovigilance Department at 866-915-6958 or FDA at 800-FDA-1088 or .1

Laboratory Monitoring

Monitor patient’s trough factor XIII activity level during treatment.1

If breakthrough bleeding occurs or expected peak plasma factor XIII activity levels not attained, perform investigation to determine presence of factor XIII inhibitory antibodies.1

Specific Populations

Pregnancy

Category C.1

Safety and efficacy during labor and delivery not established.1

Lactation

Not known whether factor XIII (human) is distributed into human milk.1 Use only when clearly needed.1

Pediatric Use

Of the 187 unique patients in the factor XIII (human) clinical studies, 90 were <16 years of age at the time of enrollment (including 16 patients <2 years of age).1

No apparent differences in safety profile compared with adults.1

Geriatric Use

Safety and efficacy in geriatric patients not established because an insufficient number of such patients has been studied.1

Common Adverse Effects

Hypersensitivity reactions (i.e., allergy, rash, pruritus, erythema), chills and/or rise in temperature, arthralgia, headache, elevated thrombin-antithrombin levels, increase in hepatic enzymes.1

Factor XIII (Human) Pharmacokinetics

Absorption

Duration

IV dose increased plasma factor XIII activity levels for approximately 28 days.1

Plasma Concentrations

Mean increase (from baseline) in plasma factor XIII activity levels after third dose (steady state) given every 28 days: 83% (range: 48–114%).1

Elimination

Half-life

5–12 days (mean: 6.6 days).7 8 9

Special Populations

Pediatric patients: Possible shorter half-life and faster clearance than in adults (based on limited number of patients).1

Stability

Storage

Parenteral

Lyophilized Concentrate for Injection

2–8°C; avoid freezing.1 Store in original carton and protect from light.1

Stable for 24 months at 2–8°C, up to the expiration date on carton and vial label.1

May store at room temperature (not to exceed 25°C) for up to 6 months.1 Mark clearly the beginning date of room temperature storage on the carton flap.1 Do not use beyond the expiration date on carton and vial labels or end of period for room temperature storage, whichever comes first.1

Do not return product to refrigerator after it has been stored at room temperature.1

Single-use vials contain no preservative; use within 4 hours after reconstitution.1 Do not refrigerate or freeze reconstituted solution.1

Actions

  • Factor XIII (human) is a heat-treated, lyophilized coagulation factor XIII concentrate made from pooled human plasma.1

  • Factor XIII, an endogenous plasma glycoprotein, consists of 2 A-subunits and 2 B-subunits.1 8 Factor XIII circulates in blood and is present in platelets, monocytes, and macrophages.1 2 Factor XIII appears in 2 forms, a heterotetrameric (A2B2) plasma protein and a homodimeric (A2) cellular form.1 6 7 8 9 10 The B-subunits in plasma have no enzymatic activity and function as carrier molecules for the A-subunits.1

  • Factor XIII is a proenzyme that is activated in the presence of calcium ion by thrombin cleavage of the A-subunit to become activated factor XIII (factor XIIIa).1 2 7

  • Factor XIIIa promotes cross-linking of fibrin during coagulation and is essential to physiologic protection of the clot against fibrinolysis.1 2 4 6 8 10 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug.1 6 8

  • Factor XIIIa catalyzes cross-linking of fibrin and α- and γ-chains for fibrin stabilization and renders the fibrin clot more elastic and resistant to fibrinolysis.1 2 6 8 Factor XIIIa also cross-links α2-plasmin inhibitor to the α-chain of fibrin, resulting in protection of the fibrin clot from degradation by plasmin.1 6 8

Advice to Patients

  • Possible risk of transmitting infectious agents (e.g., viruses, and theoretically, the CJD agent).1

  • Importance of reporting signs and symptoms of allergic hypersensitivity reactions (e.g., urticaria, rash, tightness of the chest, wheezing, hypotension, anaphylaxis) experienced during or after injection of factor XIII (human).1

  • Importance of informing patients of the signs and symptoms of immunogenicity (e.g., breakthrough bleeding).1

  • Importance of informing patients of signs and symptoms of thrombosis (e.g., swelling of limb or abdomen and/or pain; chest pain; shortness of breath; loss of sensation or motor power; altered consciousness, vision, or speech).1

  • Importance of contacting a clinician or emergency department immediately if any of the following signs and symptoms occur: shortness of breath, rash, pruritus, erythema, fainting/dizziness, chest pain, signs of thrombosis.1

  • Importance of women informing 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, 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.

Factor XIII (Human)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

number of units indicated on label

Corifact (heat-treated, precipitation/adsorption- and ion exchange chromatograph-purified; with sterile water for injection diluent, alcohol swab, and filter transfer set)

CSL Behring

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 25, 2012. 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. CSL Behring LLC. Corifact Factor XIII concentrate (human) prescribing information. Kankakee, IL; 2011 Feb.

2. Ajzner E, Schlammadinger A, Kerényi A et al. Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency. Blood. 2009; 113:723-5. [Epub 2008 Oct 27]. [PubMed 18955560]

3. Hayasi T, Kadohira Y, Morishita E et al. A case of acquired FXIII deficiency with severe bleeding symptoms. Haemophilia. 2012; 18(4):618-20. [Epub 2012 Feb 22.] [PubMed 22356719]

4. Hanafusa N, Kondo Y, Suzuki M et al. Double filtration plasmapheresis can decrease factor XIII activity. Ther Apher Dial. 2007; 11:165-70. [PubMed 17497996]

5. Luo YY, Zhang GS. Acquired factor XIII inhibitor: clinical features, treatment, fibrin structure and epitope determination. Haemophilia. 2011; 17:393-8. [Epub 2011 Feb 15]. Review. [PubMed 21323797]

6. Bagoly Z, Koncz Z, Hársfalvi J et al. Factor XIII, clot structure, thrombosis. Thromb Res. 2012; 129(3):382-7. [Epub 2011 Dec 24]. [PubMed 22197181]

7. Schroeder V, Durrer D, Meili E et al. Congenital factor XIII deficiency in Switzerland: from the worldwide first case in 1960 to its molecular characterisation in 2005. Swiss Med Wkly. 2007; 137:272-8. Review. [PubMed 17594539]

8. Karimi M, Bereczky Z, Cohan N et al. Factor XIII deficiency. Semin Thromb Hemost. 2009; 35:426-38. [Epub 2009 Jul 13]. Review. [PubMed 19598071]

9. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia. 2008; 14:1190-200. Review. [PubMed 19141159]

10. Wilmer M, Rudin K, Kolde H et al. Evaluation of a sensitive colorimetric FXIII incorporation assay. Effects of FXIII Val34Leu, plasma fibrinogen concentration and congenital FXIII deficiency. Thromb Res. 2001; 102:81-91. [PubMed 11323018]

11. Lovejoy AE, Reynolds TC, Visich JE. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood. 2006; 108:57-62. [Epub 2006 Mar 23]. [PubMed 16556896]

12. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed 2012 Aug 19.

13. Lusher J, Pipe SW, Alexander S et al. Prophylactic therapy with Fibrogammin P is associated with a decreased incidence of bleeding episodes: a retrospective study. Haemophilia. 2010; 16(2):316-21. [Epub 2009 Dec 15]. [PubMed 20017752]

14. Kitchens CS, Newcomb TF. Factor XIII. Medicine (Baltimore). 1979; 58(6):413-29. [PubMed 514066]

15. Muszbek L, Bagoly Z, Cairo A et al. Novel aspects of factor XIII deficiency. Curr Opin Hematol. 2011; 18(5):366-72. [PubMed 21738029]

16. Dargaud Y, de Mazancourt P, Rugeri L et al. An unusual clinical presentation of factor XIII deficiency and issues relating to the monitoring of factor XIII replacement therapy. Blood Coagul Fibrinolysis. 2008; 19(5):447-52. [PubMed 18600098]

17. Prenzel F, Pfäffle R, Thiele F et al. Decreased factor XIII activity during severe Henoch-Schoenlein purpura—does it play a role? Klin Padiatr. 2006; 218(3):174-6.

18. Lorenz R, Olbert P, Born P. Factor XIII in chronic inflammatory bowel diseases. Semin Thromb Hemost. 1996; 22(5):451-5. [PubMed 8989830]

19. Lorenz R, Heinmüller M, Classen M et al. Substitution of factor XIII: a therapeutic approach to ulcerative colitis. Haemostasis. 1991; 21(1):5-9. [PubMed 1677916]

20. Daly HM, Haddon ME. Clinical experience with a pasteurised human plasma concentrat in factor XIII deficiency. Thromb Haemost. 1988; 58:171-4.

21. Teich M, Longin E, Dempfle CE et al. Factor XIII deficiency associated with valproate treatment. Epilepsia. 2004; 45(2):187-9. [PubMed 14738427]

22. Shires L, Gomperts ED, Bradlow BA. An acquired inhibitor to factor XIII A case report. S Afr Med J. 1979; 56(2):70-2. [PubMed 483113]

23. Anwar R, Minford A, Gallivan L et al. Delayed umbilical bleeding--a presenting feature for factor XIII deficiency: clinical features, genetics, and management. Pediatrics. 2002; 109(2):E32. [PubMed 11826242]

24. Nugent DJ. Prophylaxis in rare coagulation disorders—factor XIII deficiency. Thromb Res. 2006; 118 Suppl 1:S23-8. [Epub 2006 Apr 17]. [PubMed 16616323]

25. Board PG, Losowsky MS, Miloszewski KJ. Factor XIII: inherited and acquired deficiency. Blood Rev. 1993; 7(4):229-42. [PubMed 8130686]

26. Asahina T, Kobayashi T, Takeuchi K et al. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv. 2007; 62(4):255-60. [PubMed 17371605]

27. Ichinose A. Hemorrhagic acquired factor XIII (13) deficiency and acquired hemorrhaphilia 13 revisited. Semin Thromb Hemost. 2011; 37(4):382-8. [Epub 2011 Jul 30]. [PubMed 21805444]

28. CSL Behring, Kankakee, IL: Personal communication.

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