Factor XIII Concentrate

Corifact, Factor XIII Concentrate (Human), is a heat-treated, lyophilized concentrate of coagulation factor XIII for reconstitution for intravenous use. Corifact (FXIII) consists of two A-subunits and two B-subunits, and is made from pooled human plasma. Each vial contains 1000-1600 units FXIII, 120 to 200 mg human albumin, 120 to 320 mg total protein, 80 to 120 mg glucose and 140 to 220 mg sodium chloride. Sodium hydroxide may have been used to adjust the pH.

All plasma used in the manufacture of Corifact is obtained from US donors and is tested using serological assays for hepatitis B surface antigen and antibodies to HIV-½ and HCV. The plasma is tested with Nucleic Acid Testing (NAT) for HCV, HIV-1, HAV and HBV and found to be non-reactive (negative), and the plasma is also tested by NAT for Human Parvovirus B19. Only plasma that passed virus screening is used for production, and the limit for Parvovirus B19 in the fractionation pool is set not to exceed 104 International Units of Parvovirus B19 DNA per mL.

Corifact is manufactured from cryo-depleted plasma into an ethanol precipitate, which is then purified by the following four steps:

• Precipitation/adsorption
• Ion exchange chromatography
• Heat-treatment (+60°C for 10 hours in an aqueous solution)
• Virus filtration over two 20 nm filters in series

The sterile filtered final bulk solution is filled into vials and lyophilized. These four manufacturing steps were independently validated in a series of in vitro experiments for their capacity to inactivate or remove both enveloped and non-enveloped viruses. Table 2 shows the virus clearance capacity of the Corifact manufacturing process, expressed as mean log reduction factor.

Table 2: Overall Virus Inactivation/Removal in Corifact

Corifact is a Factor XIII Concentrate indicated for routine prophylactic treatment and peri-operative management of surgical bleeding in adult and pediatric patients with congenital FXIII deficiency.

Dosage Forms And Strengths

Corifact is available as lyophilized powder in a single-use vial containing 1000-1600 units of Factor XIII concentrate for reconstitution. A 20 mL vial of Sterile Water for Injection, USP, is provided for reconstitution.

The actual units of potency of FXIII are stated on each Corifact vial label and carton.

Storage And Handling

• Refrigerate Corifact at 2-8°C (36-46°F). Keep in original carton to protect from light. Do not freeze.
• Corifact is stable for 36 months, up to the expiration date on the carton and vial labels. Within the expiration date, Corifact may be stored at room temperature not to exceed 25°C (77°F) for up to 6 months.
  • Do not return the product to the refrigerator after it is stored at room temperature. Clearly mark the beginning date of room temperature storage on the carton label.
  • Do not use beyond the expiration date on the carton and vial labels, or end of the period for room temperature storage, whichever comes first.
• This product does not contain a preservative and must be used within 4 hours after reconstitution. Do not refrigerate or freeze the reconstituted solution.

Manufactured by: CSL Behring GmbH, 35041 Marburg Germany, US License No. 1765. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: July 2016

Mechanism Of Action

Corifact (FXIII) is an endogenous plasma glycoprotein consisting of two A-subunits and two Bsubunits. FXIIIa promotes cross-linking of fibrin during coagulation and is essential to the physiological protection of the clot against fibrinolysis. FXIIIa is a transglutaminase enzyme that catalyzes the cross-linking of the fibrin α- and γ-chains for fibrin stabilization and renders the fibrin clot more elastic and resistant to fibrinolysis.1,2 FXIIIa also cross-links α2-plasmin inhibitor to the α-chain of fibrin, resulting in protection of the fibrin clot from degradation by plasmin. Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug.2

The B-subunits in plasma have no enzymatic activity, and function as carrier molecules for the Asubunits. They stabilize the structure of the A-subunits and protect them from proteolysis.

Pharmacokinetics

A 12-week prospective, open-label, multicenter pharmacokinetic and safety study was conducted in 7 females and 7 males with congenital FXIII deficiency, ranging in age from 5 to 42 years (3 children, 2 adolescents, 9 adults). One adult male did not complete the pharmacokinetic study.

Each subject received 40 units per kg Corifact intravenously every 28 days for a total of three doses administered at approximately 250 units per minute. Blood samples for doses 1 and 2 were drawn from patients to determine the FXIII activity level at baseline and 30 and 60 minutes after the infusion. Following the infusion of the third dose of Corifact, blood samples were drawn at regular intervals up to 28 days to determine the pharmacokinetic parameters. The mean increase in FXIII activity levels was 83% with a range of 48 to 114% over the baseline after the third dose. The pharmacokinetic parameters based on baseline adjusted FXIII activity (Berichrom assay) are shown in Table 3.

Table 3: Pharmacokinetic Parameters (n=13) by Berichrom Assay Method - Baseline Adjusted Values

Animal Toxicology And/Or Pharmacology

Corifact was studied in an acute toxicity study in mice and rats at doses up to 3550 units per kg and 1420 units per kg, respectively. Repeat dose toxicity was studied in rats at daily doses up to 350 units per kg for a period of 14 days. No signs of toxicity were observed in the single dose and repeat dose studies.

A local tolerance study in rabbits demonstrated no clinical or histopathological changes at the injection site after intravenous, intra-arterial or para-venous administration of Corifact.

A thrombogenicity test was performed in rabbits at doses up to 350 units per kg. Corifact showed no thrombogenic potential at the doses tested.

Clinical Studies

The postmarketing efficacy and safety trial conducted in 41 subjects who received routine prophylactic treatment (40 U/kg every 28 days for 52 weeks) for congenital FXIII deficiency, was to verify the clinical benefit of Corifact by showing correlation between trough levels of FXIII activity and clinical efficacy. The clinical benefit of Corifact was also demonstrated by comparing the incidence of bleeding in Corifact-treated subjects to historical control with congenital FXIII deficiency.

The incidence of spontaneous bleeding episodes requiring treatment was evaluated. Treatment was defined as an administration of a FXIII-containing product to treat the bleeding episode. None of the 5 subjects who experienced a spontaneous bleeding episode (2 nose bleeds, 2 rectal bleeds, and 1 episode of hematuria associated with a urinary tract infection, and an indwelling urinary catheter) required treatment with a FXIII-containing product.

An annualized bleeding rate of 0 episodes per subject per year for spontaneous bleeding was established when compared to a historical annualized bleeding rate of 2.5 episodes per subject per year in patients receiving on-demand treatment of acute bleeding in patients with congenital FXIII deficiency.3

Eight bleeding episodes secondary to trauma, and one associated with surgery were also reported during the 52 weeks of the trial. In the eight bleeding episodes secondary to trauma, six did not require treatment with a FXIII-containing product, and two were successfully treated with a FXIII-containing product (one was treated with Corifact and one with plasma).

The prophylactic administration of Factor XIII Concentrate (Human) every 28 days in subjects with congenital FXIII deficiency achieved mean FXIII activity levels between 5% and 20%. FXIII activity was maintained at ≥5% in ≥97% of subjects and ≥10% in ≥85% of subjects. Of the 533 doses administered to 41 subjects, dose adjustment was required on only eight occasions, supporting that 40 U/kg every 28 days is the appropriate dose for the majority of patients.

Five subjects underwent surgical procedures, four were elective and one was an emergency. Of the four elective surgeries, three subjects received Corifact prior to surgery (0 to 7 days prior to surgery) with no post-operative bleeding. One subject who received Corifact 7 days prior to surgery experienced bleeding post-extraction of all four wisdom teeth. The bleeding was stopped four hours after the oral surgery with an additional dose of Corifact (50% of the subject's routine dose). One subject who required emergency surgery was pre-treated with plasma.

REFERENCES

1. Lauer P, Metzner HJ, Zettlmeissl G, Li M, et al. Targeted Inactivation of the Mouse Locus Encoding Coagulation Factor XIII-A: Hemostatic Abnormalities in Mutant Mice and Characterization of the Coagulation Deficit. Thromb Haemost. 2002;88:967-74.

2. Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and Angiogenesis. J Thromb Haemost. 2006;4:19- 25.

3. Lusher J, Pipe SW, Alexander S, Nugent D. Prophylactic therapy with Fibrogammin P is associated with a decreased incidence of bleeding episodes: a retrospective study. Haemophilia. 2009;1-6.

The most common adverse reactions reported in frequency > 1% are joint inflammation, hypersensitivity, rash, pruritus, erythema, hematoma, arthralgia, headache, elevated thrombin-antithrombin levels, and increased blood lactate dehydrogenase.

The serious adverse reactions, reported in one subject each (frequency 0.5%), were hypersensitivity, acute ischemia, and neutralizing antibodies against FXIII.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Twelve clinical studies included a total of 188 subjects, 108 subjects were < 16 years of age [see Use in Specific Populations] and a total of approximately 4314 infusions of Corifact were administered in the studies.

A 12-month, prospective, open-label, multicenter efficacy and safety study was conducted in 25 males and 16 females ranging in age from less than 1 year to 42 years old (2 infants, 8 children, 8 adolescents, and 23 adults). There were no reports of deaths, life-threatening events, or adverse events that led to discontinuation or withdrawal from the study. Four subjects received FXIII in the peri-operative setting, and no treatment-related AEs were reported. An additional subject was pre-treated with plasma and experienced a hypersensitivity reaction.

Immunogenicity

A case of neutralizing antibodies against FXIII was reported in the postmarketing clinical study. The patient received prophylactic treatment with Corifact for ten years. Concomitant medications included interferon for hepatitis C infection. This patient presented with bruising, and post-infusion FXIII levels were found to be lower than expected. Over several weeks, FXIII recovery values decreased, so the dose and frequency of treatments were increased. Neutralizing antibodies to FXIII were detected, interferon treatment was discontinued, and the subject underwent plasmapheresis. Within a month, neutralizing antibodies were no longer detectable, FXIII recovery levels improved, and the previous prophylactic regimen was resumed.

Read the entire FDA prescribing information for Corifact (Factor XIII Concentrate (Human) Lyophilized Powder Reconstitution for Intravenous Use)