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 protein 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, increase in D dimer.

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

• Inspect the reconstituted TRETTEN visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.

• Administer at a rate not exceeding 1-2 mL per minute.

• Do not administer with other infusion solutions.

• Do not administer as drip.

This image is provided by the National Library of Medicine.

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

This image is provided by the National Library of Medicine.

Mechanism of Action

• FXIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot.

• In plasma, FXIII circulates as a heterotetramer [A2B2] composed of two FXIII A-subunits and two FXIII B-subunits held together by strong non-covalent interactions. The FXIII A is the catalytic subunit and FXIII B-subunit acts as carrier molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When FXIII A-subunit is bound to FXIII B-subunit [A2B2] the half-life of the FXIII A-subunit [A2] is prolonged. FXIII is a pro-enzyme (protransglutaminase), which is activated by thrombin in the presence of Ca2+. The enzymatic activity resides with the FXIII A-subunit. Upon activation, the FXIII A‑subunit dissociates from the FXIII B-subunit and thereby exposes the active site of the FXIII A-subunit. The active transglutaminase cross-links fibrin and other proteins resulting in increased mechanical strength and resistance to fibrinolysis of the fibrin clot and contributes to enhance platelet and clot adhesion to injured tissue.

• Coagulation Factor XIII A-Subunit (Recombinant) is a protransglutaminase (rFXIII [rA2] homodimer) and binds to free human FXIII B-subunit resulting in a heterotetramer [rA2B2] with a similar half-life to [A2B2]. rFXIII has been shown to be activated by thrombin in the presence of Ca2+. Activated rFXIII has been shown in dose-dependent manner to increase mechanical strength of fibrin clots, retard fibrinolysis, and rFXIII has been shown to enhance platelet adhesion to the site of injury. After combining with available plasma B-subunits, Coagulation Factor XIII A-subunit (Recombinant) has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII.

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.

Pharmacodynamics

• A qualitative assay of clot solubility is widely used as an indicator of FXIII deficiency; when performed correctly the test is positive only when the FXIII activity in the sample is close to zero. The results of standard coagulation tests are normal as it is the quality of the clot that is affected. In addition, at present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII.

Pharmacokinetics

Steady State in Patients with Congenital Factor XIII Deficiency

• In 23 patients with congenital FXIII A-subunit deficiency on prophylaxis, the pharmacokinetics of rFXIII were evaluated over a dosing interval of 28 days during steady state.

• The pharmacokinetic parameters based on steady state baseline adjusted FXIII activity (Berichrom assay) values are shown in Table 3.

This image is provided by the National Library of Medicine.

• At steady state, the pharmacokinetics of rFXIII are comparable with the single dose pharmacokinetics of rFXIII.

Pediatric (Ages 1 to < 6 Years Old)

• In a pharmacokinetic trial six children with congenital FXIII A-subunit deficiency on prophylaxis treatment were administered a single intravenous dose of 35 IU/kg. The pharmacokinetic parameters based on baseline adjusted FXIII activity (Berichrom assay) values are shown in Table 4. No dose adjustment is needed for pediatric patients as there is no influence of age on the pharmacokinetics of TRETTEN.

This image is provided by the National Library of Medicine.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Long-term studies in animals to evaluate the carcinogenic potential of TRETTEN, or studies to determine the effects of TRETTEN on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of TRETTEN was completed and suggests minimal carcinogenic risk from product use.

Animal Toxicology and/or Pharmacology

• Exaggerated pharmacologic effects, including general thrombosis, ischemic necrosis and mortality were observed in nonclinical studies with TRETTEN and non-proteolytically activated recombinant FXIII at a dose of 1670 IU/kg, i.e., 48 times the recommended human dose of 35 IU/kg.

• In a monkey cardiovascular safety pharmacology model evaluating the combination of excessive doses of TRETTEN (585 IU/kg, 17 times the expected human dose) in combination with rFVIIa (1000 mcg/kg, 11 times the expected human dose), one of the twelve monkeys died 4 hours after treatment due to thrombosis. Procoagulant risk factors, including 6 indwelling catheters per monkey and the induction of anesthesia, may have complicated the study results. It is unclear whether the mortality was related to the overdose of one or both products, or a specific interaction between them. Nonclinical and clinical studies with the combination of TRETTEN and rFVIIa at recommended human doses have not been performed.

Clinical Studies

• To establish the efficacy of TRETTEN for the prevention of bleeding in patients with congenital FXIII A-subunit deficiency, a multi-center, open-label, non-controlled trial was conducted for 52 weeks in forty-one (41) subjects ≥ 6 years. All subjects received monthly doses of TRETTEN at 35 IU/kg. Bleeding episodes that required treatment with a FXIII-containing product were observed to evaluate the efficacy of monthly replacement therapy with TRETTEN on prevention of bleeding episodes.

• Subjects with congenital FXIII A-subunit deficiency confirmed by genotyping were included. Subjects who before entering the trial had received regular replacement therapy were to have initiated regular replacement therapy at least 6 months prior to screening and were to have a documented history of at least one treatment-requiring bleeding episode before initiation of regular replacement therapy or a documented family history of FXIII congenital deficiency. Subjects who before entering the trial had only received on-demand treatment were to have a documented history of at least two treatment-requiring bleeding episodes within 12 months of the screening visit. Severe bleeders as defined by a documented history of ≥2 treatment requiring bleedings per year during regular FXIII replacement therapy were excluded.

• During the prophylaxis treatment period with TRETTEN (434 subject months), five bleeding episodes treated with FXIII-containing products were observed in four subjects. All five were associated with trauma. When calculated for all 41 subjects, this translated into a mean annual rate of bleeding episodes that required treatment of 0.14 [95% CI:0.058- 0.332] per subject year, which was statistically significantly lower than the historic bleeding rate of 1.68 per subject year for on-demand treatment. The age-adjusted rate of bleeding episodes that required treatment during the TRETTEN treatment period was 0.05 [95% CI: 0.0094 - 0.2501] per subject year with a model-based estimate corresponding to the mean age of 26.4 years. The mean annual bleeding rate in patients below 18 years of age was higher compared to that in adults (0.362 versus 0.040 bleeds/subject/year). Table 5 below lists the estimated bleeding rates by age.

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• Thirty-four (34) of the 41 subjects and an additional 21 new subjects were enrolled in an ongoing second trial. During a total treatment period of 107.5 subject years (mean of 1.95 years per subject), 5 subjects experienced 6 bleeds that required treatment with a FXIII-containing product. The mean annual rate of bleeding episodes that required treatment was determined to be 0.056 per subject year. The age-adjusted rate of bleeding episodes that required treatment during the TRETTEN treatment period was 0.022 per subject year [95% CI:0.0045; 0.1023] with a model-based estimate corresponding to a mean age of 29.5 years. The annual mean bleeding rate in patients below age 18 was higher compared to that in adults (0.127 versus 0.026 bleeds/subject/year) with some overlap of the respective 95% confidence intervals. Table 6 lists the estimated bleeding rates by age.

This image is provided by the National Library of Medicine.

How Supplied

• TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is supplied as a white, lyophilized powder in single-use vial along with the diluent (Sterile Water for Injection) vial.

• The actual amount of TRETTEN in international units (IU) is stated on each carton and vial. TRETTEN and the sterile water vials provided in the package are not made with natural rubber latex.

This image is provided by the National Library of Medicine.

Storage

• Store refrigerated at 2°C – 8°C (36°F – 46°F) prior to reconstitution. TRETTEN is stable until the expiration date on the carton and vial label. Do not freeze. Store protected from light.

• Use reconstituted TRETTEN within 3 hours.

• If the reconstituted product is not used immediately, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to 3 hours following reconstitution.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Discuss 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 TRETTEN.

• Discuss 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.

• Inform patients that breakthrough bleeding may be the sign and symptom of inhibitor formation.

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

• TRETTEN®

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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