TRETTEN: Package Insert and Label Information

TRETTEN- coagulation factor xiii a-subunit (recombinant)
Novo Nordisk

1 INDICATIONS AND USAGE

TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is indicated for routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.

TRETTEN is not for use in patients with congenital factor XIII B‑subunit deficiency

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

2.1 Dose

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 A2 B2 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.

TRETTEN Vial and Adapter
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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.
Remoal of the protective paper
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Attach the vial adapter
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7. Draw back the plunger of the sterile syringe and admit a volume of 3.2 mL air into the syringe.
Draw back the plunger
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8. Screw the syringe onto the vial adapter on the diluent vial.
Screw the syringe
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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.
Inject air from the plunger
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10. Remove the empty diluent vial by tipping the syringe with the attached vial adapter.
Remove the empty diluent vial
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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.
Attach the syringe to the powder vial
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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.
Gently swirl the vial
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NOTE:
For larger dose that requires multiple vials of TRETTEN, reconstitute each additional vial using the same procedure with a separate syringe.
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.
For home administration, any such changes should be communicated by the pharmacist or healthcare provider to the patient or family.

2.3 Administration

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.

3 DOSAGE FORMS AND STRENGTHS

TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is available as a white lyophilized powder in single-dose 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.

4 CONTRAINDICATIONS

TRETTEN is contraindicated in patients who have known hypersensitivity to the active substance or to any of the excipients [See Description (11)].

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

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.

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.

7 DRUG INTERACTIONS

Thrombosis may occur if TRETTEN is administered concomitantly with factor VIIa [See Nonclinical Pharmacology (13.2)].

8 USE IN SPECIFIC POPULATIONS

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.

10 OVERDOSAGE

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

11 DESCRIPTION

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-dose vial. Table 1 and Table 2 list the vial content of reconstituted TRETTEN and the diluent, respectively.

Table 1 Content of Reconstituted TRETTEN*

Content

Per Vial *

Function

Coagulation Factor XIII A-Subunit (Recombinant)

2000 — 3125 IU

Active substance

Sodium Chloride

8.70 mg

Stabilizer

Sucrose

174.0 mg

Stabilizer

Polysorbate 20

0.30 mg

Surfactant

L-Histidine

9.30 mg

Buffer

*Values are given per 3 mL reconstituted TRETTEN.

Table 2 Content of Diluent for Reconstitution of TRETTEN

Content

Per Vial

Function

Sterile Water for Injection

3.2 mL

Diluent

After reconstitution with 3.2 mL sterile water for injection, each vial contains 667-1042 IU/mL of recombinant coagulation factor XIII A-subunit. The reconstituted solution has a pH of approximately 8.0. The formulation contains no preservative and must only be administered intravenously.

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