Coagulation factor XIII A-subunit

Coagulation factor XIII A-subunit
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Overview

Coagulation factor XIII A-subunit is a {{{drugClass}}} that is FDA approved for the prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency. Common adverse reactions include headache, pain in the extremities, injection site pain, D dimer increase.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• For routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.

Dosage

• Treatment should be initiated under the supervision of a physician experienced in the treatment of rare bleeding disorders.

• The dose for routine prophylaxis for bleeding in patients with congenital factor XIII (FXIII) A-subunit deficiency is 35 international units (IU) per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay.

• Consider dose adjustment if adequate coverage is not achieved with the recommended 35 IU/kg dose.

• A pharmacokinetic study was conducted in the FXIII congenitally deficient population evaluating five dose cohorts (2, 7, 24, 60 and 89 IU/kg) with blood sampling at 0.5, 1, 4, 8, 24, 48, 72 hours, and 7, 14, and 28 days. Samples were tested for FXIII activity by a chromogenic assay and for FXIII A2B2 tetramer levels by an ELISA, as well as for other analytes. It was found that FXIII tetramer levels were proportional to the observed FXIII activity up to the point of replacement of 100% of normal FXIII activity, but there was no increase in FXIII tetramer levels at higher levels of FXIII activity. A dose of 35 IU/kg is sufficient to replace 100% of FXIII activity in this population, and higher doses may not increase the levels of tetrameric Factor XIII.

DOSAGE FORMS AND STRENGTHS

• TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is available as a white lyophilized powder in single-use vial containing nominally 2500 IU per vial (2000 – 3125 IU) of recombinant coagulation factor XIII A-subunit. The actual amount of TRETTEN in IU is stated on each carton and vial.

• After reconstitution with the provided Sterile Water for Injection, each vial contains 667-1042 IU/mL recombinant coagulation factor XIII A-subunit.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Coagulation factor XIII A-subunit in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Coagulation factor XIII A-subunit in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Coagulation factor XIII A-subunit in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Coagulation factor XIII A-subunit in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Coagulation factor XIII A-subunit in pediatric patients.

Contraindications

• TRETTEN is contraindicated in patients who have known hypersensitivity to the active substance or to any of the excipients

Warnings

Hypersensitivity Reactions

• TRETTEN may cause allergic reactions. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypotension) occur, discontinue immediately and institute appropriate treatment.

Thromboembolic Risk

• Thromboembolic complications may occur. Monitor patients with conditions that predispose to thrombosis for signs and symptoms of thrombosis after administration of TRETTEN.

Inhibitors

• Inhibitory antibodies may occur with TRETTEN. Patients with 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.

Adverse Reactions

Clinical Trials Experience

• The most common adverse reactions reported in clinical trials (≥1%), were headache, pain in the extremities, injection site pain, and increase in fibrin D dimer levels.

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.

• During clinical development, TRETTEN was administered to 77 patients with congenital factor XIII A-subunit deficiency (3:2, male: female ratio) for a total of 1990 doses. Fifty patients (65%) were between the ages of 18 and 77 years (received 1338 doses), 21 patients (27%) were between the ages of 6 and less than 18 years old (received 560 doses), and 6 patients (8%) were less than 6 years old (received 92 doses). Patients were exposed for up to 4.5 years.

• Of the 77 patients, 68 received 1979 monthly doses of 35 IU/kg of TRETTEN for routine prophylaxis of bleeding. Eleven single doses of TRETTEN have been administered to nine patients for pharmacokinetic investigations.

• The adverse drug reactions reported included headache, pain in the extremities, pain at the injection site, and increase in fibrin D dimer levels (without evidence of thromboembolic events).

Immunogenicity

• The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRETTEN with the incidence of antibodies to other products may be misleading.

• Low level, non-neutralizing antibodies were seen in four of the 77 patients with congenital FXIII A-subunit deficiency. They were all under the age of 18 years. Three of these patients discontinued from trial after development of antibodies. All four patients received at least two doses, with at least one dose given subsequent to the formation of the non-neutralizing antibodies. These antibodies were not found to be of clinical significance.

• In another study including 50 healthy subjects (29 males, 21 females), who were given 2 doses of TRETTEN, one subject developed low-titer, transient non-neutralizing antibodies after receiving the first dose of TRETTEN. The antibodies had no inhibitory activity, and the antibodies disappeared in the 6-month follow up.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Coagulation factor XIII A-subunit in the drug label.

Drug Interactions

• Thrombosis may occur if TRETTEN is administered concomitantly with factor VIIa

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Coagulation factor XIII A-subunit in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Coagulation factor XIII A-subunit during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Coagulation factor XIII A-subunit with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Coagulation factor XIII A-subunit with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Coagulation factor XIII A-subunit with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Coagulation factor XIII A-subunit with respect to specific gender populations.

Race

There is no FDA guidance on the use of Coagulation factor XIII A-subunit with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Coagulation factor XIII A-subunit in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Coagulation factor XIII A-subunit in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Coagulation factor XIII A-subunit in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Coagulation factor XIII A-subunit in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous

Monitoring

There is limited information regarding Monitoring of Coagulation factor XIII A-subunit in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Coagulation factor XIII A-subunit in the drug label.

Overdosage

• One patient accidentally received a dose 2.3 times the recommended dose. No clinical signs and symptoms were observed.

Pharmacology

There is limited information regarding Coagulation factor XIII A-subunit Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Coagulation factor XIII A-subunit Mechanism of Action in the drug label.

Structure

TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is a recombinant human factor XIII-A2 homodimer composed of two factor XIII (FXIII) A-subunits. The FXIII A-subunit is a 731 amino acid chain with an acetylated N-terminal serine. When FXIII is activated by thrombin, a 37 amino acid peptide is cleaved from the N-terminus of the A‑subunit.

TRETTEN is manufactured as an intracellular, soluble protein in yeast (Saccharomyces cerevisiae) production strain containing the episomal expression vector, pD16. It is subsequently isolated by homogenization of cells and purification by several chromatography steps, including hydrophobic interaction and ion exchange chromatography. No human or animal derived products are used in the manufacturing process.

TRETTEN is supplied as a sterile, white lyophilized powder in a single use vial. Table 1 and Table 2 list the vial content of reconstituted TRETTEN and the diluent, respectively.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Coagulation factor XIII A-subunit in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Coagulation factor XIII A-subunit in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Coagulation factor XIII A-subunit in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Coagulation factor XIII A-subunit in the drug label.

How Supplied

Storage

There is limited information regarding Coagulation factor XIII A-subunit Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Coagulation factor XIII A-subunit in the drug label.

Precautions with Alcohol

• Alcohol-Coagulation factor XIII A-subunit interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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