2.1 Dose

• 40 International Units (IU) per kg body weight at a rate not to exceed 4 mL per minute
• Adjust dose ±5 IU per kg to maintain 5% to 20% trough level of FXIII activity as provided in the example below

2.2 Administration

• Administer at a rate not exceeding 4 mL per minute
• For routine prophylaxis, administer every 28 days
• For peri-operative management of surgical bleeding:
  • Dosing should be individualized based on the patient's FXIII activity level, type of surgery, and clinical response
  • Monitor patient's FXIII activity levels during and after surgery
  • Following are dose adjustment examples for peri-operative management in reference to the patient's last prophylactic dose:

The potency expressed in International Units is determined using the Berichrom activity assay, referenced to the current International Standard for Blood Coagulation Factor XIII, Plasma.

2.3 Reconstitution

Perform a visual inspection of the reconstituted solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The procedures below are provided as general guidelines for the preparation and reconstitution of CORIFACT.

Reconstitute CORIFACT at room temperature as follows:

1. Ensure that the CORIFACT vial and diluent vial are at room temperature.
2. Place the CORIFACT vial, diluent vial, and Mix2Vial® transfer set on a flat surface.
3. Remove CORIFACT and diluent vial flip caps. Wipe the stoppers with an alcohol swab and allow the stoppers to dry prior to opening the Mix2Vial transfer set package.
4. Open the Mix2Vial transfer set package by peeling away the lid (Fig. 1). Leave the Mix2Vial transfer set in the clear package.
   

   Fig. 1

5. Place the diluent vial on a flat surface and hold the vial tightly. Grip the Mix2Vial transfer set together with the clear package and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial (Fig. 2).
   

   Fig. 2

6. Carefully remove the clear package from the Mix2Vial transfer set. Make sure that you pull up only the clear package, not the Mix2Vial transfer set (Fig. 3).
   

   Fig. 3

7. With the CORIFACT vial placed firmly on a flat surface, invert the diluent vial with the Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the CORIFACT vial (Fig. 4). The diluent will automatically transfer into the CORIFACT vial.
   

   Fig. 4

8. With the diluent and CORIFACT vial still attached to the Mix2Vial transfer set, gently swirl the CORIFACT vial to ensure that the CORIFACT is fully dissolved (Fig. 5). Do not shake the vial.
   

   Fig. 5

9. With one hand, grasp the CORIFACT side of the Mix2Vial transfer set and with the other hand grasp the blue diluent-side of the Mix2Vial transfer set, and unscrew the set into two pieces (Fig. 6).
   

   Fig. 6

10. Draw air into an empty, sterile syringe. While the CORIFACT vial is upright, screw the syringe to the Mix2Vial transfer set. Inject air into the CORIFACT vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly (Fig. 7).
    

    Fig. 7

11. Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial transfer set (Fig. 8). Attach the syringe to a suitable intravenous administration set.
    

    Fig. 8

12. If patient requires more than one vial, pool the contents of multiple vials into one syringe. Use a separate unused Mix2Vial transfer set for each product vial.
13. CORIFACT is for dose use only. Contains no preservatives. The product must be used within 4 hours after reconstitution. Do not refrigerate or freeze the reconstituted solution. Discard partially used vials.

5.1 Hypersensitivity

Hypersensitivity reactions have been observed with CORIFACT. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypotension) occur, immediately discontinue administration [see Patient Counseling Information (17)] and institute appropriate treatment.

5.2 Immunogenicity

Development of inhibitory antibodies against FXIII has been detected in patients receiving CORIFACT. Monitor patients for development of inhibitory antibodies. Presence of inhibitory antibodies may manifest as an inadequate response to treatment. If expected plasma FXIII activity levels are not attained, or if breakthrough bleeding occurs while receiving prophylaxis, perform an assay that measures FXIII inhibitory antibody concentrations.

5.3 Thromboembolic Risk

Thromboembolic complications have been reported. Monitor patients with known risk factors for thrombotic events.

5.4 Transmission of Infectious Agents

Because CORIFACT is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens.

All infections thought by a physician to have been possibly transmitted by this product are to be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

5.5 Monitoring Laboratory Tests

• Monitor patient's trough FXIII activity level during treatment with CORIFACT [see Dosage and Administration (2.2)].
• If breakthrough bleeding occurs, or if expected peak plasma FXIII activity levels are not attained, perform an investigation to determine the presence of FXIII inhibitory antibodies [see Clinical Pharmacology (12.3)].

6.1 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 (8.4)] and a total of approximately 4314 infusions of CORIFACT were administered in the studies. The most common adverse reactions occurring at a rate of 1-2% are outlined [see Adverse Reactions (6)].

6.2 Immunogenicity

A case of neutralizing antibodies against FXIII was reported in an open enrollment 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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Of the 188 subjects in the CORIFACT clinical studies, 108 were subjects <16 years of age at the time of enrollment (see Table 3).

In the pharmacokinetic study [see Clinical Pharmacology (12.3)], 5 of the 14 subjects ranged in age from 2 to <16 years. Subjects less than 16 years had a shorter half-life (5.7 ± 1.00 days) and faster clearance (0.29 ± 0.12 mL/hr/kg) compared to adults (half-life: 7.1 ± 2.74 days, clearance: 0.22 ± 0.07 mL/hr/kg). Dose adjustments may be needed for patients <16 years of age. There were no differences in the safety profile in children as compared to adults.

8.5 Geriatric Use

Clinical studies of CORIFACT did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or another drug therapy.

12.1 Mechanism of Action

CORIFACT (FXIII) is an endogenous plasma glycoprotein consisting of two A-subunits and two B-subunits. 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.2,3 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.3

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

12.2 Pharmacodynamics

Administration of CORIFACT to patients with congenital FXIII deficiency replaces missing or low levels of coagulation Factor XIII, enabling a temporary correction of the factor deficiency and correction of bleeding tendencies. There are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII. The results of standard coagulation (clot time-based) tests are normal in FXIII deficient patients as it is the quality of the clot that is affected. A qualitative assay of clot suitability is used as an indicator of FXIII deficiency; when performed correctly the test is positive only when the FXIII activity in the sample is close to zero. Thromboelastography can also be affected by FXIII deficiency.

12.3 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 5.

13.2 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.

Pharmacokinetic Study

The accelerated approval of CORIFACT was based on a pharmacokinetic study in 13 subjects with congenital FXIII deficiency evaluating three doses at 40 units per kg every 28 days for each subject. Maintaining FXIII activity trough level between 5%-20% is predicted to provide clinical benefit. Twelve out of thirteen subjects (92%) attained trough FXIII levels of ≥ 5%. based on standard Berichrom assay [see Clinical Pharmacology (12.3)].

The post marketing efficacy and safety trial was a prospective, multicenter, open-label study 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 bleeding outcomes. 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. This study included 18 subjects (44%) who were less than 16 years of age and 23 subjects (56%) who were ≥16 to <65 years. Two subjects were 1 month to <2 years of age, 8 subjects were 2 years to <12 years, and 8 subjects were 12-16 years of age.

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.4

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.

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.
• Discard any unused product and all used disposable supplies.