Recombinant factor XIII A-subunit is used for the routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency. Factor XIII is the terminal enzyme in the blood coagulation cascade and is composed of 2 factor XIII A-subunits and 2 factor XIII B-subunits. The enzymatic activity resides in factor XIII A-subunits. Recombinant factor XIII A-subunit is manufactured as an intracellular, soluble protein in yeast cells. No human or animal products are involved in the manufacturing process of recombinant factor XIII A-subunit.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Each vial contains 2,000 to 3,125 International Units. Check the vial to be used for actual factor XIII A-subunit content.
-After reconstitution, each vial contains 667 to 1,042 International Units/mL recombinant factor XIII A-subunit.
Reconstitution
-The factor XIII A-subunit and diluent vial must be at room temperature prior to reconstitution.
-Remove the flip caps of the factor XIII A-subunit vial and diluent vial, swab with alcohol, and allow time to dry.
-Remove the protective paper from the vial adapter, but do not unscrew the protective cap. Attach the vial adapter to the diluent vial. Once attached, remove the protective cap from the vial adapter by gently squeezing the protective cap with thumb and index finger.
-Admit 3.2 mL of air into the sterile syringe and then screw the syringe onto the vial adapter on the diluent vial. Inject the air into the diluent vial and withdraw 3.2 mL water into the syringe. Remove the empty diluent vial by tipping the syringe with the attached vial adapter.
-Attach the syringe with the vial adapter to the powder vial. Hold the syringe slightly tilted with the vial facing downward. Push the plunger slowly to inject 3.2 mL water into the powder vial. To avoid foaming, do not inject the diluent directly onto the powder.
-Gently swirl the vial until powder is dissolved. Do not shake the vial.
-After reconstitution, the solution should be colorless.
-For larger doses requiring multiple vials, reconstitute each additional vial using the same technique and new syringe.
-For small doses requiring less than the full volume of the vial, reconstituted solution may be diluted with normal saline to facilitate measurement of small volumes.
-Storage: After reconstitution, use immediately. If not used immediately, the product may be stored at room temperature or refrigerated for up to 3 hours. Discard any unused portion after 3 hours.
Intravenous injection
-Do not mix with any other infusion solutions.
-Administer at a rate not exceeding 1 to 2 mL/minute.
-Do not administer as a continuous infusion.
Headache, pain in the extremities, pain at the injection site, and increase in fibrin D dimer concentrations (without evidence of thromboembolic events) were reported in 1% or more of patients during clinical trials with recombinant factor XIII A-subunit.
Transient, non-neutralizing antibody formation was seen in 1 of 50 healthy subjects after 1 dose, 4 of 77 subjects with congenital factor XIII-A subunit deficiency after 1 or 2 doses, and in 1 subject in a postmarketing safety study after 3.5 years of treatment; the 5 patients with factor XIII-A subunit deficiency were under the age of 18 years. The antibodies were not found to be of any clinical significance. No subjects developed neutralizing antibodies during clinical trials.
Recombinant factor XIII A-subunit is contraindicated for use in patients with known hypersensitivity to the active substance or to any of the excipients. Signs and symptoms of hypersensitivity reactions may include urticaria, chest tightness, rash, wheezing, hypotension, and anaphylaxis during or after recombinant factor XIII A-subunit receipt. Immediately discontinue administration and initiate appropriate treatment if a hypersensitivity reaction occurs.
The safety and efficacy of recombinant factor XIII A-subunit has not been established in geriatric patients due to an insufficient number of patients studied.
Thromboembolic disease complications may occur with the administration of recombinant factor XIII A-subunit. Monitor patients with conditions that predispose to thrombosis for signs and symptoms of thrombosis after administration of recombinant factor XIII A-subunit.
Inhibitory antibodies to recombinant factor XIII A-subunit may develop during treatment. If plasma factor XIII activity concentrations are not achieved or if breakthrough bleeding occurs while on therapy, factor XIII inhibitors may have developed. Prescribers should perform an assay that measures factor XIII antibody concentrations.
There are no adequate and well-controlled studies using recombinant factor XIII A-subunit during human pregnancy to determine a drug-associated risk. Animal reproduction studies have not been conducted with recombinant factor XIII A-subunit.
There is no information regarding the presence of recombinant factor XIII A-subunit in human milk, the effect on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for recombinant factor XIII A-subunit and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.
For routine bleeding prophylaxis in patients with congenital factor XIII A-subunit deficiency:
Intravenous dosage:
Adults: 35 International Units/kg IV once monthly to achieve a target trough concentration of factor XIII activity of 10% or more using a validated assay. Consider dose adjustment if adequate coverage is not achieved with the recommended dose; however, higher doses may not increase the concentrationss of factor XIII if already achieved replacement of 100% of normal factor XIII activity.
Infants, Children, and Adolescents: 35 International Units/kg IV once monthly to achieve a target trough concentration of factor XIII activity of 10% or more using a validated assay. Consider dose adjustment if adequate coverage is not achieved with the recommended dose; however, higher doses may not increase the concentrations of factor XIII if already achieved replacement of 100% of normal factor XIII activity.
Neonates: 35 International Units/kg IV once monthly to achieve a target trough concentration of factor XIII activity of 10% or more using a validated assay. Consider dose adjustment if adequate coverage is not achieved with the recommended dose; however, higher doses may not increase the concentrations of factor XIII if already achieved replacement of 100% of normal factor XIII activity.
Maximum Dosage Limits:
Specific maximum dosage information is not available. Individualize dosage based on body weight and laboratory values.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Factor VIIa, Recombinant: (Major) Concomitant use of recombinant factor XIII A-subunit with factor VIIa, recombinant may result in thrombosis. However, no clinical or nonclinical human studies have been performed with recombinant factor XIII A-subunit and recombinant factor VIIa at recommended human doses. Simultaneous use of factor VIIa, recombinant and recombinant factor XIII A-subunit should be avoided due to the potential for thrombosis.
Factor XIII is an endogenous plasma glycoprotein that circulates in the blood as 2 factor XIII A-subunits and 2 factor XIII B-subunits. The enzymatic activity resides in the A-subunit; the B-subunit is the carrier molecule for A-subunit in circulation. Factor XIII is a proenzyme that becomes activated by thrombin in the presence of calcium. When activated, the A-subunit dissociates from the B-subunit, exposing the active site of the A-subunit. During the coagulation cascade, factor XIII promotes cross-linking of fibrin and other proteins, which strengthens the clot and hinders fibrinolysis, and enhances platelet adhesion to the site of injury. Recombinant factor XIII A-subunit has been shown to have the same pharmacodynamic properties in plasma as endogenous factor XIII.
Recombinant factor XIII A-subunit is administered intravenously. Pharmacokinetic parameters were evaluated in 23 patients (age: 7 to 58 years) over a dosing interval of 28 days during steady state. Parameters, based on steady state baseline adjusted factor XIII activity, were as follows: Vd = 65.9 (+/- 26.9) mL/kg, Cmax = 0.71 (+/- 0.17) International Units/mL, clearance = 0.33 mL/kg/hour, half-life = 5.1 (+/- 2.6) days. Mean residence time was 7.9 (+/- 3.4) days. Single dose and steady state pharmacokinetic parameters are comparable.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Special Populations
Pediatrics
The pharmacokinetics of recombinant factor XIII A-subunit are comparable in children, adolescents, and adults. Although half-life is longer and clearance is faster in young children compared to older pediatric patients and adults, these differences are not thought to be clinically significant. In a small pharmacokinetic study in pediatric patients (n = 6, age: 1 to 5 years), mean pharmacokinetic parameters, based on baseline adjusted factor XIII activity, were as follows: Vd = 61.2 (+/- 41) mL/kg, Cmax = 0.48 (+/- 0.14) International Units/mL, clearance = 0.41 (+/- 0.2) mL/kg/hour, half-life = 7.1 (+/- 1.9) days. Mean residence time was 7.5 (+/- 4.8) days.