Corifact: Package Insert and Label Information

CORIFACT- factor xiii concentrate (human)
CSL Behring GmbH

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

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
Table 1. Dose Adjustment Using the Berichrom Activity Assay
FXIII Activity Trough Level (%) Dosage Change
One trough level of <5% Increase by 5 IU per kg
Trough level of 5% to 20% No change
Two trough levels of >20% Decrease by 5 IU per kg
One trough level of >25% Decrease by 5 IU per kg

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:
Table 2. Dose Adjustment for Peri-operative Management
Time Since Last Dose Dose
Within 7 days Additional dose may not be needed
8 – 21 days Additional partial or full dose may be needed based on FXIII activity level
21 – 28 days Full 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.
    Figure 1
    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).
    Figure 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).
    Figure 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.
    Figure 4
    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.
    Figure 5
    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).
    Figure 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).
    Figure 7
    (click image for full-size original)
    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.
    Figure 8
    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.
Figure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7Figure 8

3 DOSAGE FORMS AND STRENGTHS

CORIFACT is available as lyophilized powder in a single-dose 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.

4 CONTRAINDICATIONS

CORIFACT is contraindicated in patients with known anaphylactic or severe systemic reactions to human plasma-derived products [see Description (11)].

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials (>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 (frequency 0.5%), were hypersensitivity, acute ischemia, and neutralizing antibodies against FXIII [see Warnings and Precautions 5)].

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Animal reproduction studies have not been conducted with CORIFACT.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations: Disease-associated maternal and/or embryo/fetal risk

Miscarriage is a known complication of congenital FXIII deficiency with a rate of 91% observed in 136 pregnancies without routine FXIII supplementation prophylaxis and 11% in 45 pregnancies with routine FXIII prophylaxis1.

8.2 Lactation

Risk Summary

There is no information available on the presence of CORIFACT in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CORIFACT and any potential adverse effects on the breastfed child from CORIFACT or from the underlying maternal condition.

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).

Table 3. Pediatric Subjects in CORIFACT Clinical Studies
Age Group Subjects(n)
<1 month 2
1 month to <2 years 16
2 to 11 years 60
12 to <16 years 30

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.

11 DESCRIPTION

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-1/2 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 4 shows the virus clearance capacity of the CORIFACT manufacturing process, expressed as mean log10 reduction factor.

Table 4. Overall Virus Inactivation/Removal in CORIFACT
Manufacturing Steps Virus Reduction Factor (log10 )
Enveloped Viruses Non-Enveloped Viruses
HIV BVDV WNV PRV HAV CPV
HIV, Human immunodeficiency virus type 1, model for HIV-1 and HIV-2BVDV, bovine viral diarrhea virus, model for HCVWNV, West Nile virusPRV, pseudorabies virus, a model for large enveloped DNA virusesHAV, Hepatitis A virusCPV, canine parvovirus, model for B19VB19V, Human parvovirus B19N/A, not applicablen.d., not done
*
Not included in the calculation of the overall virus reduction factor.
Studies using human parvovirus B19, which are considered experimental in nature, have demonstrated a virus reduction factor of ≥4.0 log10 by heat treatment.
Al(OH)3 Adsorption / Vitacel® and Defibrination n.d. n.d. n.d. 6.9 n.d. n.d.
Ion Exchange Chromatography 5.0 3.3 n.d. ≥8.0 3.4 3.7
Heat Treatment ≥7.7 ≥8.1 ≥7.4 N/A * 4.3 1.0
20 nm / 20 nm Virus Filtration ≥6.1 ≥5.0 ≥7.4 ≥6.4 ≥5.6 6.1
Cumulative Virus Reduction (log10 ) ≥18.8 ≥16.4 ≥14.8 ≥21.3 ≥13.3 10.8
Page 1 of 3 1 2 3

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2020. All Rights Reserved.