(factor xiii concentrate (human))
[CSL Behring GmbH]
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CORIFACT safely and effectively. See full prescribing information for CORIFACT.
Corifact, Factor XIII Concentrate (Human)
Lyophilized powder for solution for injection
For intravenous use only.
Initial U.S. Approval: 2011
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Corifact is a Factor XIII concentrate indicated for adult and pediatric patients with congenital Factor XIII deficiency for:
DOSAGE AND ADMINISTRATION
For intravenous use only.
Dose Adjustment Using the Berichrom Activity Assay (2.1)
Dose Adjustment for Peri-operative Management
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION
2 DOSAGE AND ADMINISTRATION
Dose Adjustment Using the Berichrom Activity Assay
|Factor XIII 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|
|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.
The procedures below are provided as general guidelines for the preparation and reconstitution of Corifact.
Reconstitute Corifact at room temperature as follows:
3 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.
Corifact is contraindicated in patients with known anaphylactic or severe systemic reactions to human plasma-derived products [see Description (11)].
5 WARNINGS AND PRECAUTIONS
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.
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
Corifact is made from human plasma. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, 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 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 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.
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.
Efficacy and Safety Study
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.
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.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Animal reproduction studies have not been conducted with Corifact. Safety and effectiveness in pregnancy have not been established. It is also not known whether Corifact can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Corifact should be given to a pregnant woman only if clearly needed.
8.2 Labor and Delivery
Corifact has not been studied for use during labor and delivery. Safety and effectiveness in labor and delivery is unknown.
8.3 Nursing Mothers
It is not known whether Corifact is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Corifact is administered to a nursing woman.
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 1).
|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.
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:
- 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 log10 reduction factor.
|Manufacturing Steps||Virus Reduction Factor (log10)|
|Enveloped Viruses||Non-Enveloped Viruses|
|HIV, Human immunodeficiency virus type 1, model for HIV-1 and HIV-2|
|BVDV, bovine viral diarrhea virus, model for HCV|
|WNV, West Nile virus|
|PRV, pseudorabies virus, a model for large enveloped DNA viruses|
|HAV, Hepatitis A virus|
|CPV, canine parvovirus, model for B19V|
|B19V, Human parvovirus B19|
|N/A, not applicable|
|n.d., not done|
|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|
|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|
12 CLINICAL PHARMACOLOGY
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.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 A-subunits. They stabilize the structure of the A-subunits and protect them from proteolysis.
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.
|AUC ss, (0-inf) = Area under the plasma concentration curve from time 0 to infinity at steady state|
|Css, max: Peak concentration at steady state|
|Css, min: Trough concentration at steady state|
|Tmax: Time to peak concentration|
|Vss: Volume of distribution at steady state|
|MRT = Mean residence time|
|SD = Standard deviation|
|AUC ss, 0-inf (units•hr/mL)||184.0 ±65.78|
|Css, max (units/mL)*||0.9 ±0.20|
|Css, min (units/mL)*||0.05 ±0.05|
|Tmax (hr)||1.7 ±1.44|
|Half-life [days]||6.6 ±2.29|
|CL [mL/hr/kg]||0.25 ±0.09|
|Vss [mL/kg]||51.1 ±12.61|
|MRT [days]||10.0 ±3.45|
13 NONCLINICAL TOXICOLOGY
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.
14 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.
- 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.
- Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and Angiogenesis. J Thromb Haemost. 2006;4:19-25.
- 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
|Presentation||Carton NDC Number||Components|
16.2 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 24 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.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information)
- Inform patients of the signs and symptoms of allergic hypersensitivity reactions, such as urticaria, rash, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of Corifact [see Warnings and Precautions (5.1)].
- Inform patients of the signs and symptoms of immunogenicity such as breakthrough bleeding [see Warnings and Precautions (5.2)].
- Inform patients of signs and symptoms of thrombosis, such as limb or abdomen swelling and/or pain, chest pain, shortness of breath, loss of sensation or motor power, altered consciousness, vision, or speech [see Warnings and Precautions (5.3)].
- Inform patients that because Corifact is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent [see Warnings and Precautions (5.4) and Description (11)].
Factor XIII Concentrate (Human)
FDA-Approved Patient Labeling – Patient Product Information (PPI)
This leaflet summarizes important information about Corifact. Please read it carefully before using Corifact and each time you get a refill. There may be new information provided. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about Corifact. If you have any questions after reading this, ask your healthcare provider.
What is Corifact?
Corifact is an injectable medicine used for routine prophylactic treatment and peri-operative management of surgical bleeding in adults and pediatric patients with congenital Factor XIII (FXIII) deficiency. Corifact is a coagulation FXIII concentrate made from human plasma, and has important functions in hemostasis (stopping of bleeding).
Who should not use Corifact?
You should not use Corifact if you have experienced hypersensitivity (allergy) reactions, including anaphylactic or severe systemic reactions to human plasma-derived products.
What should I tell my healthcare provider before Corifact is given?
Tell your healthcare provider about all of your medical conditions, including:
- If you are pregnant or planning to become pregnant. It has not been established if Corifact can harm your unborn baby.
- Labor and Delivery: Safety and effectiveness in labor and delivery have not been established.
- Breast feeding: It has not been established if Corifact passes into your milk.
Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and non-prescription medicines such as over-the-counter medicines, supplements, or herbal remedies.
How is Corifact given?
Corifact is administered into your vein (intravenous injection). Before infusing, Corifact is dissolved using sterile water provided in the package. Your healthcare provider will prescribe the dose that you receive.
What could be the possible side effects of Corifact?
Call your healthcare provider or the emergency department right away if you have any of the following symptoms after using Corifact:
- shortness of breath
- pruritus (itching)
- erythema (redness of the skin)
- chest pain
- signs of a blood clot including pain, swelling, warmth, redness, or a lump in your legs or arms.
Other possible side effects may include:
- chills/rise in temperature
- arthralgia (joint pain)
- breakthrough bleeding and pain resulting from formation of antibodies against Corifact.
Because Corifact is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent.
These are not all the possible side effects of Corifact.
Tell your healthcare provider about any side effect that bothers you or that does not go away. You can also report side effects to the FDA at 1-800-FDA-1088.
What else should I know about Corifact?
Medicines are sometimes prescribed for purposes other than those listed here. Do not use Corifact for a condition for which it is not prescribed. Do not share Corifact with other people, even if they have the same symptoms that you have.
This leaflet summarizes the most important information about Corifact. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Corifact that was written for healthcare professionals.
Talk to your healthcare provider before traveling.
CSL Behring GmbH
35041 Marburg Germany
US License No. 1765
CSL Behring LLC
Kankakee, IL 60901 USA
Revised: January 2013
PRINCIPAL DISPLAY PANEL - Single-Use Vial Label
Factor XIII Concentrate (Human)
For Intravenous Use Only
Each Corifact® single-use vial contains 1000–1600
International Units (units) of lyophilized Factor XIII
concentrate for reconstitution with 20 mL of Sterile
Water for Injection, USP. Store Corifact® in a refrigerator
at 2–8°C (36–46°F). Corifact® is stable for 24 months,
up to the expiration date on the carton and vial labels.
Do not use if the reconstituted solution is cloudy or
contains particulates. Do not freeze. Protect from light.
Contains no preservative.
factor xiii concentrate (human) kit
|Labeler - CSL Behring GmbH (326530474)|
|CSL Behring GmbH||326530474||MANUFACTURE(63833-518)|