2.1 Dose

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

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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.

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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.

2.2 Reconstitution

Reconstitute only with sterile water for injection (provided with TRETTEN). The product can be reconstituted using the vial adapter included or a needle.

Reconstitute using the following procedures:

 

1. Use aseptic technique.

 

2. Wash hands before starting.

 

3. Bring TRETTEN (white lyophilized powder) and sterile water for injection (diluent) to room temperature, but not above 25°C (77°F).

 

4. Remove the plastic caps from the two vials.

 

5. Clean the rubber stoppers on the vials with sterile alcohol swabs and allow them to dry before use.

 

6. Remove the protective paper from the vial adapter, but do not unscrew the protective cap. Attach the vial adapter to the diluent vial, without taking the vial adapter out of the protective cap. Once attached, remove the protective cap from the vial adapter by lightly squeezing the protective cap with your thumb and index finger as shown on the figure below.

 

7. Draw back the plunger of the sterile syringe and admit a volume of 3.2 mL air into the syringe.

 

8. Screw the syringe onto the vial adapter on the diluent vial.

 

9. Inject the air from the syringe into the diluent vial until resistance is felt. Then hold the syringe with the diluent vial upside down and withdraw 3.2 mL water into the syringe.

 

10. Remove the empty diluent vial by tipping the syringe with the attached vial adapter.

 

11. Attach the syringe with the vial adapter to the powder vial. Hold the syringe slightly tilted with vial facing downwards. Push the plunger slowly to inject all water (3.2 mL) into the powder vial. Do not inject the diluent directly on the TRETTEN powder to avoid foaming.

 

12. Gently swirl the vial until all material is dissolved. Do not shake the vial. The reconstituted TRETTEN is a clear and colorless solution. Use the reconstituted TRETTEN immediately. If not, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to three hours. Discard after three hours.

 

NOTE:

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For larger dose that requires multiple vials of TRETTEN, reconstitute each additional vial using the same procedure with a separate syringe.

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For smaller dose that requires less than the full volume in the vial, reconstituted TRETTEN may be diluted with 0.9% sodium chloride to facilitate measurement of small volumes. Discard remaining product.

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For home administration, any such changes should be communicated by the pharmacist or healthcare provider to the patient or family.

2.3 Administration

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

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

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Do not administer with other infusion solutions.

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Do not administer as drip.

5.1 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.

5.2 Thromboembolic Risk

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

5.3 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.

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.

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

Of the 77 subjects, 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 subjects 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.

Transient non-neutralizing antibodies were seen in one out of 50 healthy subjects after one dose, four out of 77 trial subjects (age < 18 years) with congenital factor XIII A-subunit deficiency after one or two doses (3 discontinued from the trial), and in one subject (age < 18 years) in a post marketing safety study after 3.5 years of treatment. In two subjects, the non-neutralizing antibodies disappeared after continued treatment with TRETTEN. In all cases, the non-neutralizing antibodies were found to be of no clinical significance. No subjects developed neutralizing antibodies (inhibitors) against TRETTEN during clinical trials.

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies using TRETTEN in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with TRETTEN.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Miscarriage is a known complication of congenital FXIII deficiency. Pooling data from 39 publications, the miscarriage rate was 66% in 63 patients with 192 pregnancies (70% in 179 pregnancies in FXIII A-subunit deficiency women). Miscarriage rate was 91% in the 136 pregnancies without routine prophylaxis with FXIII concentrates and 11% in the 45 pregnancies treated with routine FXIII prophylaxis2.

8.2 Lactation

Risk Summary

There is no information regarding the presence of TRETTEN in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRETTEN and any potential adverse effects on the breastfed infant from TRETTEN or from the underlying maternal condition.

8.4 Pediatric Use

Pediatric subjects in the phase 3 study and the extension study included 6 children in the age range 0-5, 12 children in the age range 6-12, and 9 adolescents in the age range 13-17 who were treated with TRETTEN for a total of 652 exposures. Adverse reactions were more frequently reported in subjects aged from 6 to less than 18 years old than in adults; a greater number of possible/probably trial drug related events were reported in the subjects below 18 years of age (6 subjects with 11 events in 27 enrolled subjects) than in those above 18 years (3 subjects with 3 events in 41 enrolled subjects). Three subjects under 18 years experienced non-neutralizing antibodies and were withdrawn from the study.  A fourth pediatric subject who had a non-neutralizing antibody remained in the trial. No dose adjustment is required for pediatric age group.

8.5 Geriatric Use

The safety and efficacy of TRETTEN in the geriatric population have not been established due to an insufficient number of patients.

12.1 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.

12.2 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.

12.3 Pharmacokinetics

Steady State in Subjects with Congenital Factor XIII Deficiency

In 23 subjects 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.

 

Table 3 Pharmacokinetic parameters based on steady state baseline adjusted FXIII activity

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.

 

Table 4 The pharmacokinetic parameters based on baseline adjusted FXIII activity

13.1 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.

13.2 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.