Review of Selected NMEs 2014

Jack DeRuiter, PhD; Pamela L. Holston, RPh, BS, BA; Taylor Joseph DeRuiter, PharmD Candidate


US Pharmacist. 2014;39:HS-2-HS-15. 

In This Article

Coagulation Factor XIII A-subunit (Recombinant) (Tretten, Novo Nordisk)

Indication and Clinical Profile6

Coagulation factor XIII A-subunit (recombinant) (rFXIII-A) was approved as an orphan drug under the FDA's accelerated approval program for prevention of bleeding in patients with congenital factor XIII A-subunit (FXIII-A) deficiency. FXIII-A deficiency is a rare genetic disorder in which an increased incidence of bleeding results from insufficient synthesis of factor XIII, which is involved in normal clotting. rFXIII-A is the first recombinant product approved for bleeding prophylaxis in adults and children with FXIII-A deficiency.

FDA approval of rFXIII-A was based on a multicenter, open-label, noncontrolled trial in 41 patients aged ≥6 years with known congenital FXIII-A deficiency confirmed by genotyping. All patients received a monthly 35-IU/kg dose of rFXIII-A. Patients had initiated regular replacement therapy ≥6 months before trial entry and had fewer than two treatment-requiring bleeds per year or previously had received only on-demand treatment and had a documented history of at least two treatment-requiring bleeding episodes within the last year. The number of bleeding episodes requiring treatment with an FXIII-containing product was observed, and the mean annual rate of bleeding episodes per subject-year was determined and compared with the historical control group's estimated bleeding rate. rFXIII-A patients experienced a mean annual rate of bleeding episodes requiring treatment of 0.14 per subject-year, a statistically significant improvement from the historic bleeding rate of 1.68 per subject-year in patients receiving on-demand treatment only. Currently, 34 of these patients and 21 new patients are enrolled in an ongoing second trial that has thus far reported a mean annual rate of bleeding episodes requiring treatment of 0.056 per subject-year.

Pharmacology and Pharmacokinetics6

rFXIII-A is a recombinant form of the catalytic subunit of FXIII, which is the terminal enzyme in the coagulation cascade. FXIII circulates in plasma as a heterotetramer composed of two FXIII A-subunits that function as the catalytic subunit and two FXIII B-subunits that function as carrier molecules. When FXIII is activated by thrombin in the presence of calcium, the A-subunit dissociates from the B-subunit, exposing its active site, which cross-links fibrin and other proteins. This results in a clot with increased mechanical strength and resistance to fibrinolysis, as well as enhanced platelet and clot adhesion.

rFXIII-A has peak plasma concentrations of 0.71 IU/mL and 0.48 IU/mL. It is cleared at a rate of 0.33 mL/h/kg and 0.41 mL/h/kg in adults and children, respectively. It has a respective prolonged half-life of 5.1 days and 7.1 days in adults and children owing to its ability to bind with free B-subunits of FXIII, which protect the drug from inactivation.

Adverse Reactions and Drug Interactions6

The most common adverse reactions (≥1%) reported in clinical trials were headache, pain in extremities, injection-site pain, and elevated fibrin D-dimer levels. No thromboembolic complications were reported during trials; however, such complications may occur, and patients receiving rFXIII-A should be monitored for signs and symptoms of thrombosis, especially if they have conditions that increase the risk of thrombosis formation. The risk of thrombosis is increased if rFXIII-A is administered concomitantly with factor VIIa. During therapy, inhibitory antibodies to rFXIII-A may occur that could result in inadequate response to treatment. An assay measuring FXIII inhibitory antibody concentrations should be performed if breakthrough bleeding occurs or adequate plasma FXIII activity levels are not attained during treatment.

This drug should be given during pregnancy only if it is clearly needed, as it is not known whether rFXIII-A can affect reproductive capacity or causes fetal harm when given during pregnancy (Pregnancy Category C). It should be noted that, during clinical trials, one patient accidentally received 2.3 times the recommended dosage and no clinical signs and symptoms were observed.

Dosage and Administration6

rFXIII-A is supplied as a white lyophilized powder in single-use vials containing 2,000 to 3,125 IU per vial (actual amount stated on each carton and vial), along with a vial of Sterile Water for Injection as a diluent. After reconstitution, each vial contains 667 to 1,042 IU/mL of rFXIII-A to be administered IV at the recommended dosage of 35 IU/kg by a physician or via self-administration. rFXIII-A should be stored away from light and refrigerated at 2°C to 8°C prior to reconstitution. After reconstitution, the solution should be used immediately, but may be stored at 25°C if used within 3 hours. No dosage adjustment is necessary for pediatric patients; however, these patients experienced a greater frequency of adverse reactions. The safety and efficacy of rFXIII-A in elderly patients are not established. rFXIII-A should be discontinued immediately if signs or symptoms of anaphylaxis or hypersensitivity reactions occur.