Factor XIII A-Subunit (Recombinant) (Monograph)

Brand name: Tretten
Drug class: Hemostatics
VA class: BL500
Chemical name: Human Factor XIII [A2] homodimer (allele F13A*1B), recombinant DNA origin
Molecular formula: C₃₇₀₈H₅₇₃₅N₁₀₁₃O₁₁₁₁S₂₈
CAS number: 606138-08-3

Introduction

Biosynthetic (recombinant DNA origin) preparation of human factor XIII A₂ homodimer consisting of 2 factor XIII A-subunits.

Uses for Factor XIII A-Subunit (Recombinant)

Congenital Factor XIII A-subunit Deficiency

Routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency; designated an orphan drug by FDA for such use.

Prophylactic therapy with factor XIII concentrate is recommended in all patients with severe (<1% factor XIII activity) deficiency; considered current standard of care.

Factor XIII concentrate currently available in the US as a plasma-derived (Corifact) and a recombinant (Tretten) preparation. Some experts recommend preferential use of recombinant preparations because of potentially superior safety profile with respect to pathogen transmission. When selecting an appropriate factor XIII preparation, consider characteristics of each clotting factor concentrate in addition to individual patient variables.

Not effective and should not be used in patients with factor XIII B-subunit deficiency.

Factor XIII A-Subunit (Recombinant) Dosage and Administration

Administration

IV Administration

Administer by slow IV injection. (See Rate of Administration under Dosage and Administration.) Do not administer by continuous IV infusion.

Initiate therapy under supervision of a clinician experienced in the treatment of rare bleeding disorders. May be self-administered in the home setting after appropriate training provided.

Do not administer in the same IV line with other infusion solutions.

Reconstitution

Reconstitute lyophilized drug with sterile water for injection provided by manufacturer. Prior to reconstitution, allow drug vial and diluent to warm to (but not exceed) room temperature (25°C). To avoid foaming, do not inject diluent directly onto powder. Gently swirl vial; do not shake. Resulting solution should be clear and colorless; discard if particulate matter or discoloration observed.

May dilute solution with 0.9% sodium chloride injection to facilitate measurement of small doses (volumes) for administration.

Administer immediately after reconstitution or within 3 hours. If not used immediately, store in refrigerator or at room temperature (not to exceed 25°C). Discard unused portion.

Consult manufacturer's information for additional details on reconstitution and preparation of the drug.

Rate of Administration

Administer at a rate not exceeding 1–2 mL/minute.

Dosage

Dosage expressed in international units (IU, units). Each vial contains 2000–3125 units of factor XIII A-subunit (recombinant); actual number of units indicated on each vial and carton.

Individualize dosage based on factor XIII activity and clinical response. Dosage adjustments based on age not required.

Administer once a month to maintain trough factor XIII activity levels ≥10% (as measured by a validated assay). Pharmacokinetic studies indicate that a dose of 35 units/kg is sufficient to replace 100% of factor XIII activity; since factor XIII A₂B₂ tetramer levels increase proportionately with observed factor XIII activity up to 100%, higher doses may not result in further increases in factor XIII A₂B₂ tetramer levels.

Pediatric Patients

Congenital Factor XIII A-subunit Deficiency

IV

35 units/kg once monthly. Consider dosage adjustment if bleeding not adequately controlled.

Adults

Congenital Factor XIII A-subunit Deficiency

IV

35 units/kg once monthly. Consider dosage adjustment if bleeding not adequately controlled.

Cautions for Factor XIII A-Subunit (Recombinant)

Contraindications

• Known hypersensitivity reactions to factor XIII A-subunit (recombinant) or any of its components.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Risk of hypersensitivity reactions (e.g., urticaria, rash, chest tightness, wheezing, hypotension).

If manifestations of anaphylaxis or hypersensitivity occur, immediately discontinue drug and initiate appropriate treatment.

Thromboembolic Complications

Risk of thromboembolic complications. Although not observed with factor XIII A-subunit (recombinant), has been reported with plasma-derived factor XIII concentrates.

In patients with an underlying risk of thrombosis, monitor for thromboembolic complications.

Immunogenicity

Neutralizing antibodies (inhibitors) to factor XIII may develop after treatment with factor XIII A-subunit (recombinant). May manifest as inadequate response to treatment.

Monitor for possible development of inhibitory antibodies. If expected plasma factor XIII activity levels not attained or bleeding occurs during factor XIII A-subunit (recombinant) prophylaxis, perform appropriate assay to detect presence of inhibitors.

Transient, low-titer non-neutralizing antibodies detected in pediatric patients receiving factor XIII A-subunit (recombinant); clinically important effects not observed.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether distributed into human milk. Use caution.

Pediatric Use

Pediatric patients 0–17 years of age have received factor XIII A-subunit (recombinant) in clinical studies. Adverse effects were reported more frequently in children 6 to <18 years of age than in adults. (See Immunogenicity under Cautions.)

Pharmacokinetic parameters are similar across different age groups, including in pediatric patients.

Geriatric Use

Safety and efficacy not established in geriatric patients.

Common Adverse Effects

Headache, extremity pain, injection site pain, increased fibrin D dimer levels.

Drug Interactions

Specific Drugs

Factor XIII A-Subunit (Recombinant) Pharmacokinetics

Absorption

Duration

After IV administration of 35 units/kg, plasma factor XIII activity increases to adequate levels and normal clot solubility is restored for approximately 28–30 days.

Plasma Concentrations

After IV administration, plasma concentrations increase in dose-dependent manner.

Distribution

Extent

Remains principally within intravascular space.

Not known whether distributed into human milk.

Elimination

Half-life

Approximately 5–15 days.

Stability

Storage

Parenteral

Powder for Injection

2–8°C; avoid freezing. Protect from light.

Reconstituted solutions: May store in refrigerator or at room temperature (≤25°C) for up to 3 hours after reconstitution.

Actions

• Biosynthetic (recombinant DNA origin) preparation of human factor XIII A₂ homodimer (consists of 2 factor XIII A-subunits).

• Congenital factor XIII deficiency is a rare but serious bleeding disorder manifested by a lifelong bleeding tendency that typically includes umbilical bleeding during the neonatal period, delayed soft tissue bleeding, mucosal bleeding, poor wound healing, recurrent miscarriage, and intracranial hemorrhage. Predominantly caused by deficiency of the factor XIII A-subunit; factor XIII B-subunit deficiency is extremely rare and associated with milder clinical manifestations.

• Patients with congenital factor XIII A-subunit deficiency have decreased plasma levels of endogenous factor XIII A-subunit, resulting in a hemorrhagic tendency. Factor XIII A-subunit (recombinant) restores normal clot solubility in such patients.

• Factor XIII is a proenzyme (protransglutaminase) that is activated in the presence of calcium by thrombin; once activated, factor XIIIa promotes cross-linking of fibrin and other proteins (α₂-plasmin inhibitor, fibrinogen, collagen) to strengthen and stabilize the fibrin clot, protect from fibrinolysis, and enhance platelet adhesion to the site of tissue injury.

• Factor XIII circulates in plasma as a heterotetrameric glycoprotein consisting of 2 A-subunits and 2 B-subunits (A₂B₂). The A-subunit is the active catalytic domain; B-subunits function as carrier molecules for A-subunits.

• Factor XIII A-subunit (recombinant) binds to free, noncomplexed factor XIII B-subunit to form A₂B₂. In its complexed form, pharmacodynamic and pharmacokinetic (e.g., half-life) properties of factor XIII A-subunit (recombinant) are similar to endogenous factor XIII.

• Prepared using DNA technology in a yeast (Saccharomyces cerevisiae) expression system and further purified through several chromatography steps (e.g., hydrophobic interaction, ion exchange chromatography). Manufactured without any human or animal components.

Advice to Patients

• Importance of advising patients to read the manufacturer's patient information (patient information and instructions for use).

• Importance of patients reporting to their clinician any adverse reactions or other issues occurring after administration of factor XIII A-subunit (recombinant).

• Risk of hypersensitivity reactions; importance of informing patients of manifestations (e.g., urticaria, rash, chest tightness, wheezing, hypotension, anaphylaxis) that may occur during or after administration of factor XIII A-subunit (recombinant).

• Importance of informing patients of signs and symptoms of thrombosis (e.g., swelling and/or pain of limb or abdomen; chest pain; shortness of breath; loss of sensation or motor power; alteration in consciousness, vision, or speech).

• Importance of advising patients that bleeding occurring during factor XIII A-subunit (recombinant) prophylaxis may be a sign of neutralizing antibody (inhibitor) formation.

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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