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Corifact

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

Introduction

Preparation of blood coagulation factor XIII derived from pooled human plasma.1 7 8

Uses for Corifact

Congenital Factor XIII Deficiency

Routine prophylaxis and perioperative management of bleeding in patients with congenital factor XIII deficiency;1 7 8 13 14 15 29 31 33 34 36 designated an orphan drug by FDA for treatment of congenital factor XIII deficiency.12

Initial FDA-labeled use based on trough factor XIII levels (5–20%) as a surrogate measure of efficacy; clinical benefit (i.e., prevention of bleeding episodes) established in a postmarketing study.1 29 33

Prophylactic therapy with factor XIII concentrates is recommended in all patients with severe (<1% factor XIII activity) deficiency; considered current standard of care.7 8 25 34 38

Currently available factor XIII concentrates in the US include a plasma-derived (Corifact) and a recombinant (Tretten) preparation.1 10 30 31 Some experts recommend preferential use of recombinant preparations because of their potentially superior safety profile with respect to pathogen transmission.30 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions.) When selecting an appropriate factor XIII preparation, consider characteristics of each clotting factor concentrate in addition to individual patient variables.32

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

Corifact Dosage and Administration

Administration

IV Administration

Administer by slow IV injection.1 (See Rate of Administration under Dosage and Administration.)

Reconstitution

Reconstitute lyophilized powder with manufacturer-supplied sterile water for injection diluent.1 Prior to reconstitution, allow drug and diluent to warm to room temperature.1 Gently swirl vial; do not shake.1

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

Rate of Administration

Administer at a rate not exceeding 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); actual number of units indicated on each vial and carton.1

Individualize dosage based on factor XIII levels, presence and severity of bleeding, and clinical response.1 35 (See Laboratory Monitoring under Cautions.)

Initial dose of 40 units/kg recommended; adjust subsequent dose in increments or decrements of 5 units/kg based on trough factor XIII activity levels.1 (See Table 1.)

Table 1. Dose Adjustment Using the Berichrom Activity Assay

Trough Factor XIII Activity

Dose 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

Pediatric Patients

Congenital Factor XIII Deficiency

Dosage adjustment in pediatric patients <16 years of age may be required due to age-related differences in pharmacokinetics.1 (See Special Populations under Pharmacokinetics.)

Routine Prophylaxis of Bleeding
IV

40 units/kg every 28 days.1 Adjust dosage to maintain factor XIII levels of 5–20%.1 (See Table 1.)

Perioperative Management of Bleeding
IV

Additional dosing may be necessary in patients undergoing surgery depending on the timing of their last prophylactic dose.1 Individualize dosing requirements based on type of surgery, factor XIII activity, and clinical response.1 36

If last prophylactic dose given within 7 days of surgery, additional dose generally not needed.1

If last prophylactic dose given 8–21 days previously, an additional partial or full dose is recommended depending on factor XIII levels.1

If last prophylactic dose was given 21–28 days previously, an additional full dose is recommended.1

Adults

Congenital Factor XIII Deficiency
Routine Prophylaxis of Bleeding
IV

40 units/kg every 28 days.1 Adjust dosage to maintain factor XIII levels of 5–20%.1 (See Table 1.)

Perioperative Management of Bleeding
IV

Additional dosing may be necessary in patients undergoing surgery depending on the timing of their last prophylactic dose.1 Individualize dosing requirements based on type of surgery, factor XIII activity, and clinical response.1 36

If last prophylactic dose given within 7 days of surgery, additional dose generally not needed.1

If last prophylactic dose given 8–21 days previously, an additional partial or full dose is recommended depending on factor XIII levels.1

If last prophylactic dose was given 21–28 days previously, an additional full dose is recommended.1

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 Corifact

Contraindications

  • Known anaphylactic or severe systemic reactions to human plasma-derived products.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, chest tightness, wheezing, hypotension) occur.1

Immunogenicity

Although frequency low,34 inhibitory antibodies against factor XIII detected in patients receiving factor XIII (human).1 2 Presence of inhibitory antibodies 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.1 Closely monitor patients with known risk factors.1

Risk of Transmissible Agents in Plasma-derived Preparations

Factor XIII (human) is prepared from human blood and may carry risk of transmitting infectious agents (e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent).1 Also potentially capable of transmitting unknown infectious agents.1

Report any suspected infections associated with 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 Also monitor during and after surgery.1 34

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 however, has been used throughout pregnancy in some women with congenital factor XIII deficiency to prevent spontaneous abortion and obstetrical hemorrhagic complications.7 8 16 26

Lactation

Not known whether factor XIII (human) is distributed into human milk.1 Use caution.1

Pediatric Use

Has been used in some children <2 years up to 16 years of age.1

No apparent differences in safety profile in children compared with adults.1 However, differences in pharmacokinetic profile observed; dosage adjustments may be necessary in patients <16 years of age.1 (See Special Populations under Pharmacokinetics.)

Geriatric Use

Safety and efficacy in geriatric patients not established.1

Common Adverse Effects

Hypersensitivity reactions (i.e., rash, pruritus, erythema), joint inflammation, hematoma, arthralgia, headache, elevated thrombin-antithrombin levels, increased blood LDH.1

Interactions for Corifact

No formal drug interaction studies to date.28

Corifact Pharmacokinetics

Absorption

Duration

IV dose results in 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).1 7 8 9

Special Populations

Patients <16 years: Possible shorter half-life and faster clearance than in adults.1

Stability

Storage

Parenteral

Powder 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 (≤25°C) for up to 6 months.1 Do not use beyond the expiration date on carton and vial labels or beyond the period of room temperature storage, whichever comes first.1

Do not return product to refrigerator after storage at room temperature.1

Reconstituted solutions: Use within 4 hours after reconstitution.1 Do not refrigerate or freeze.1

Actions

  • Preparation of blood coagulation factor XIII derived from pooled human plasma.1

  • Congenital factor XIII deficiency is a rare but serious bleeding disorder manifested by a lifelong bleeding tendency that typically includes umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding, poor wound healing, recurrent miscarriage, and intracranial hemorrhage.7 9 10 13 14 16 20 23 24 27 34

  • Factor XIII circulates in plasma as a heterotetrameric glycoprotein consisting of 2 A-subunits and 2 B-subunits.1 8 Enzymatic activity resides in the A-subunit; B-subunits function as carrier molecules for the A-subunits.1 6 7 8 9 10

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

  • Factor XIIIa promotes cross-linking of fibrin and other proteins, resulting in a fibrin clot that is more elastic and resistant to fibrinolysis.1 2 4 6 8 10

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

  • Importance of reporting signs and symptoms of 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 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Factor XIII (Human)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

number of units indicated on label

Corifact (with sterile water for injection diluent; available with alcohol swab and filter transfer set)

CSL Behring

AHFS DI Essentials. © Copyright 2017, Selected Revisions February 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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; 2013 Jan.

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 9028951]

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 9598071]

9. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia. 2008; 14:1190-200. Review. [PubMed 9141159]

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 1323018]

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. [PubMed 16688675]

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 166163223]

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.

29. Food and Drug Administration. Summary Basis for Regulatory Action: STN BLA#125385/0. From FDA website.

30. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendation regarding the use of recombinant clotting factor products with respect to pathogen transmission (May 6, 2014). MASAC recommendation #226. From National Hemophilia Foundation website.

31. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (revised April 2014). MASAC recommendation #225. From National Hemophilia Foundation website.

32. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding factor concentrate prescriptions and formulary development and restrictions (March 12, 2005). MASAC recommendation #159. From National Hemophilia Foundation website.

33. Ashley C, Chang E, Davis J et al. Efficacy and safety of prophylactic treatment with plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency. Haemophilia. 2015; 21:102-8. [PubMed 25377187]

34. Bolton-Maggs PH, Perry DJ, Chalmers EA et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia. 2004; 10:593-628. [PubMed 15357789]

35. Nugent DJ, Ashley C, García-Talavera J et al. Pharmacokinetics and safety of plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency. Haemophilia. 2015; 21:95-101. [PubMed 25458735]

36. Janbain M, Nugent DJ, Powell JS et al. Use of Factor XIII (FXIII) concentrate in patients with congenital FXIII deficiency undergoing surgical procedures. Transfusion. 2015; 55:45-50. [PubMed 25070582]

38. Acharya SS. Rare bleeding disorders in children: identification and primary care management. Pediatrics. 2013; 132:882-92. [PubMed 24127475]

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