VA Class:BL500
Factor XIII (human) is a preparation of blood coagulation factor XIII derived from pooled human plasma.1, 7, 8
Congenital Factor XIII Deficiency
Factor XIII (human) is used for 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 the drug has been designated an orphan drug by FDA for the treatment of congenital factor XIII deficiency.12
Congenital factor XIII deficiency is a rare but serious bleeding disorder manifested by a lifelong hemorrhagic 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 The clinical severity of factor XIII deficiency varies based on plasma concentrations of the coagulation factor.34 Patients at highest risk of severe spontaneous bleeding generally have less than 1% of normal activity, while those with factor XIII levels exceeding 5% may have only occasional bleeding episodes.34 Prophylactic therapy with factor XIII concentrates is recommended at the time of diagnosis and considered the current standard of care in all patients with severe (less than 1% factor XIII activity) congenital factor XIII deficiency.7, 8, 25, 34, 38 Fresh frozen plasma and cryoprecipitate also have been used in the treatment of factor XIII deficiency but generally are considered less satisfactory alternatives to factor XIII concentrates because of the risk of blood-borne diseases.8, 31
Currently available factor XIII concentrates in the US include a plasma-derived (Corifact®) and a recombinant (Tretten®) preparation.1, 30, 31 Because these preparations vary based on characteristics such as purity, half-life, recovery, method of manufacture, viral removal/inactivation processes, potential immunogenicity, and other attributes, they are not pharmacologically or therapeutically equivalent.32 Some experts (e.g., the Medical and Scientific Advisory Council [MASAC] of the National Hemophilia Foundation) recommend preferential use of recombinant clotting factor concentrates because of their potentially superior safety profile with respect to pathogen transmission.30 Although improved viral depleting and donor screening practices with currently available plasma-derived concentrates have greatly reduced the risk of transmission of human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV), these preparations are potentially capable of transmitting other disease agents such as nonenveloped viruses (e.g., parvovirus B19) and prions (e.g., causative agent for Creutzfeldt-Jakob disease [CJD] and variant CJD [vCJD]).30 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Warnings/Precautions.) When selecting an appropriate factor XIII preparation, clinicians should consider the characteristics of each clotting factor concentrate in addition to individual patient variables.32 In all patients, the potential risk of pathogen transmission must be weighed against the benefits of therapy.30
Factor XIII (human) became commercially available in the US under the principles and procedures of the accelerated review policy of the FDA, which allows approval based on analysis of surrogate markers of response rather than clinical end points.29 Initial FDA-labeled use of factor XIII (human) was therefore based on trough factor XIII levels (5-20%) as a surrogate measure of efficacy; clinical benefit (e.g.1 , prevention of bleeding episodes) was later demonstrated in a subsequent postmarketing study.29, 33 In this prospective, open-label study, 41 patients with congenital factor XIII deficiency received routine prophylaxis with factor XIII (human) 40 units/kg every 28 (±2) days for 52 weeks (mean treatment duration of 338 days).1, 29, 33 Such prophylactic therapy effectively achieved and maintained factor XIII levels within the target range of 5-20%, and these levels correlated with clinical response.1, 29, 33 Spontaneous bleeding events (epistaxis, rectal bleeding, hematuria) occurred in 5 patients, but none required treatment with a factor XIII-containing preparation.1, 33 The annualized bleeding rate in patients receiving prophylactic factor XIII (human) therapy was substantially lower than the bleeding rate in a historical control group receiving on-demand treatment (0 versus 2.5 episodes per patient/year).1, 29, 33 In 4 patients who underwent an elective surgical procedure, factor XIII (human) effectively maintained hemostasis in all but one patient when administered 0-7 days prior to surgery; this patient required an additional dose of factor XIII (human) (at 50% of the usual dose) to control postoperative bleeding.1, 29, 33 Experience with the use of plasma-derived factor XIII concentrate in patients with congenital factor XIII deficiency also has been reported outside the US (e.g., Europe), principally in open-label trials and case studies.7, 8, 9, 13, 14, 15, 16, 20, 23, 24, 25, 26
Acquired Factor XIII Deficiency
Factor XIII (human) also has been used to treat acquired factor XIII deficiency†, a condition associated with various diseases and other conditions (e.g., inflammatory bowel/autoimmune diseases, Henoch-Schonlein purpura, leukemia, adverse effects of certain drugs [e.g., isoniazid, penicillin, phenytoin, valproic acid], autoantibody against the A or B subunit of factor XIII).2, 3, 5, 9, 17, 18, 19, 21, 22, 25 In addition to therapy with factor XIII (human), patients with acquired factor XIII deficiency† associated with autoantibodies against factor XIII have received adjunctive therapy with immunosuppressant drugs (e.g., cyclosporine, cyclophosphamide) to eradicate these antibodies.8, 27
Unopened vials of factor XIII (human) should be stored in the original carton (to protect from light) in a refrigerator at 2-8°C; the vials should not be frozen.1 When stored as directed, factor XIII (human) is stable for 24 months, up to the expiration date on the carton and vial labels.1 Within the expiration date, factor XIII (human) may be stored at room temperature (not exceeding 25°C) for up to 6 months.1 The beginning date of room temperature storage should be clearly marked on the carton label.1 Factor XIII (human) should not be used beyond the expiration date on the carton and vial labels, or after the end of the period of room temperature storage, whichever comes first.1
Reconstitution and Administration
Factor XIII (human) is administered by slow IV injection.1 (See Rate of Administration under Dosage and Administration: Reconstitution and Administration.)
Commercially available vials of factor XIII (human) contain no preservatives and are for single use only.1 Prior to use, the lyophilized factor XIII (human) powder for injection should be reconstituted with sterile water for injection diluent according to the manufacturer's directions.1 Both the drug and diluent vial should be allowed to reach room temperature prior to reconstitution.1 Following addition of the diluent, the vial should be gently swirled to ensure complete dissolution of the powder; the vial should not be shaken.1 Reconstituted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1
Reconstituted solutions of factor XIII (human) should be administered within 4 hours after reconstitution; partially used vials should be discarded.1 The reconstituted solution should not be refrigerated or frozen.1
Factor XIII (human) should be administered at a rate not exceeding 4 mL per minute.1
Dosage of factor XIII (human) is expressed in international units (IU, units) of factor XIII activity.1 Each vial contains 1000-1600 units of factor XIII (human); the actual number of units of factor XIII activity is indicated on each vial label and carton.1
Congenital Factor XIII Deficiency
Dosage of factor XIII (human) for the treatment of patients with congenital factor XIII deficiency should be individualized based on factor XIII levels, presence and severity of bleeding, and clinical response.1, 35 (See Laboratory Monitoring under Cautions: Warnings/Precautions.)
The recommended initial dosage of factor XIII (human) in patients with congenital factor XIII deficiency is 40 units/kg every 28 days.1 Subsequent doses should be adjusted in increments or decrements of 5 units/kg based on factor XIII levels to achieve and maintain trough levels within the range of 5-20%.1 The manufacturer recommends the following guidelines for adjusting dose.1 (See Table 1.)
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 |
Patients younger than 16 years of age may have different dosing requirement than adults because of differences in pharmacokinetics.1 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
In patients receiving routine prophylaxis with factor XIII (human) who undergo surgery, additional doses may be necessary depending on the timing of their last prophylactic dose.1 Dosing requirements during the perioperative period should be individualized based on the type of surgery, factor XIII levels, and clinical response.1, 36 An additional dose of factor XIII (human) generally is not necessary if the last prophylactic dose was given within 7 days of surgery.1 However, if the last prophylactic dose was given 8-21 days previously, an additional partial or full dose of factor XIII (human) is recommended depending on the patient's factor XIII levels; if the last prophylactic dose was given 21-28 days previously, an additional full dose is recommended.1
In pregnant women, administration of factor XIII (human) concentrate to achieve plasma factor XIII activity levels of at least 2-3% (ideally exceeding 10%) during early gestation and greater than 30% during labor has been suggested.8, 9 The timing and optimum dosage of factor XIII (human) concentrate for maintenance of successful pregnancy has not been fully elucidated.8
Factor XIII (human) is contraindicated in patients with known anaphylactic or severe systemic reactions to human plasma-derived products.1
Hypersensitivity reactions (including allergy, rash, pruritus, and erythema) have occurred in patients receiving factor XIII (human).1 If manifestations of anaphylaxis or hypersensitivity reactions (e.g., urticaria, rash, chest tightness, wheezing, and hypotension) occur, administration of factor XIII (human) should be immediately discontinued and appropriate treatment instituted.1
Although the frequency is considered to be low,34 inhibitory antibodies against factor XIII have been detected in patients receiving factor XIII (human).1 In a postmarketing clinical study of factor XIII (human), a patient who received prophylaxis for 10 years developed neutralizing antibodies against factor XIII.1 Concomitant drugs taken by the patient included interferon for hepatitis C infection.1 The patient developed bruising and upon testing, post-infusion factor XIII levels were lower than expected.1 Over several weeks, factor XIII recovery values decreased so the dose and frequency of treatments were increased.1 Neutralizing antibodies to factor XIII (human) were detected, interferon treatment was discontinued, and the patient underwent plasmapheresis.1 Within a month, neutralizing antibodies were no longer detectable, factor XIII recovery levels improved, and the previous prophylactic regimen was resumed.1
The presence of inhibitory antibodies to factor XIII may manifest as an inadequate response to treatment.1, 2 Patients receiving factor XIII (human) should be monitored for possible development of inhibitory antibodies.1 If expected plasma factor XIII activity levels are not attained, or if breakthrough bleeding occurs during prophylaxis, an assay that measures factor XIII inhibitory antibody concentrations should be performed.1
Thromboembolic complications have been reported in patients receiving factor XIII (human).1 Patients with known risk factors for thrombosis should be closely monitored.1
Risk of Transmissible Agents in Plasma-derived Preparations
Factor XIII (human) is prepared from pooled human plasma, and therefore may carry a risk of transmitting infectious agents (e.g., viruses and, theoretically, the causative agent for Creutzfeldt-Jakob disease [CJD]).1 Plasma-derived preparations are also potentially capable of transmitting unknown or emerging viruses or other disease pathogens.1
Any suspected infections associated with factor XIII (human) therapy should be reported to CSL Behring Pharmacovigilance Department at 866-915-6958 or to FDA at 800-FDA-1088 or [Web].1
Monitoring of the patient's trough factor XIII activity level is recommended during treatment with factor XIII (human) to guide dosing and assess response to therapy.1 Monitoring of factor XIII levels also is recommended during and after surgery.1, 34 If breakthrough bleeding occurs, or if expected peak plasma factor XIII activity levels are not attained, an investigation to determine the presence of factor XIII inhibitory antibodies should be performed.1 (See Immunogenicity under Cautions: Warnings/Precautions.)
Category C.1 (See Users Guide.) Although safety and efficacy of factor XIII (human) have not been established in pregnant women,1 the drug has been used throughout pregnancy in some women with congenital factor XIII deficiency to prevent spontaneous abortion and obstetrical bleeding complications.7, 8, 16, 26
Safety and efficacy of factor XIII (human) in labor and delivery have not been established.1
It is not known whether factor XIII (human) is distributed into human milk.1 Because many drugs are distributed into milk, the drug should be used with caution in nursing women.1
Of the 188 patients in the factor XIII (human) clinical studies, 108 were younger than 16 years of age at the time of enrollment (including 18 patients younger than 2 years of age).1 In a pharmacokinetic study, 5 of the 14 patients ranged in age from 2 to younger than 16 years of age.1 Patients younger than 16 years of age had a shorter mean half-life (5.7 days) and faster mean clearance (0.29 mL/hour per kg) compared with adults (half-life: 7.1 days, clearance: 0.22 mL/hour per kg); dosage adjustments may be necessary in this pediatric age group.1 There were no apparent differences in the safety profile of factor XIII (human) in children compared with adults.1
The safety and efficacy of factor XIII (human) in geriatric patients have not been established.1
Adverse effects reported in more than 1% of patients receiving factor XIII (human) in clinical trials included joint inflammation, hypersensitivity reactions (i.e., rash, pruritus, erythema), hematoma, arthralgia, headache, elevated thrombin-antithrombin levels, and increased blood lactate dehydrogenase.1
Factor XIII (human) is a preparation of blood coagulation factor XIII derived from pooled human plasma.1 All plasma used in the manufacture of factor XIII (human) is obtained from US donors and is tested using serologic assays for hepatitis B surface antigen and antibodies to human immunodeficiency virus-1 (HIV-1), HIV-2, and hepatitis C virus (HCV).1 The plasma also is tested with nucleic acid testing for HCV, HIV-1, hepatitis A virus (HAV), hepatitis B virus (HBV), and parvovirus B19.1 Factor XIII (human) is isolated from human plasma by ethanol precipitation and further purified using a series of viral inactivation/removal steps, including precipitation/adsorption, ion exchange chromatography, heat treatment (60°C for 10 hours in aqueous solution), and filtration.1
Factor XIII circulates in plasma as a heterotetrameric glycoprotein consisting of 2 A-subunits and 2 B-subunits.1, 6, 7, 8, 9, 10 Enzymatic activity resides in the A-subunits; the B-subunits function as carrier molecules for the A-subunits, stabilizing and protecting them from proteolysis.1
Factor XIII is a proenzyme that is activated in the presence of calcium ions by thrombin cleavage of the A-subunit; upon activation, 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, 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 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic plug.1, 6, 8
In a 12-week, open-label pharmacokinetic and safety study in 14 patients 5-42 years of age with congenital factor XIII deficiency, the mean increase in factor XIII activity levels after the third 40-unit/kg dose (i.e., at steady state) was 83% (range: 48-114%) compared with baseline.1 Mean half-life of the drug was approximately 6.6 days in these patients.1, 7, 8, 9
Importance of informing patients that factor XIII (human) may carry a risk of transmitting infectious agents.1 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Warnings/Precautions.)
Importance of reporting signs and symptoms of hypersensitivity reactions (e.g., urticaria, rash, chest tightness, 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 and/or pain of limb or abdomen; chest pain; shortness of breath; loss of sensation or motor power; alteration in consciousness, vision, or speech).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.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
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) |
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 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 et al. Factor XIII deficiency. Semin Thromb Hemost . 2009; 35:426-38. [Epub 2009 Jul 13.] Review. [PubMed 19598071][Web]
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]
12. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website ([Web]). Accessed 2012 Aug 20
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? . 2006; 218(3):174-6.
18. Lorenz R, Olbert P, Born P. Fa Klin Padiatr ctor 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. Inbal A, Muszbek L. Coagulation factor deficiencies and pregnancy loss. Semin Thromb Hemost . 2003; 29(2):171-4. [PubMed 12709920]
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.
29. Food and Drug Administration. Summary Basis for Regulatory Action: STN BLA#125385/0. From FDA website. [Web]
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. [Web]
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. [Web]
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. [Web]
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]