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 eva luating 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 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.

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with TRETTEN. It is also not known whether TRETTEN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TRETTEN should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether TRETTEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRETTEN is administered to a nursing woman.

8.4 Pediatric Use

Pediatric patients 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 patients 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 patients below 18 years of age (6 patients with 11 events in 27 enrolled patients) than in those above 18 years (3 patients with 3 events in 41 enrolled patients). Three patients under 18 years experienced non-neutralizing antibodies and were withdrawn from the study.  A fourth pediatric patient 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 patiens.