RECOTHROM (Page 2 of 3)

6.2 Immunogenicity

The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with the results from other products due to differences in assay methodology, patient populations, and other underlying factors.

The potential for development of antibodies to RECOTHROM thrombin was evaluated in multiple clinical trials and included patients with a single exposure to RECOTHROM as well as patients who were re-exposed to RECOTHROM during a subsequent surgical procedure. Only patients with both baseline and post-treatment antibody specimens available were evaluated for the development of specific anti-RECOTHROM product antibodies, which was defined as seroconversion or a ≥1.0 titer unit (≥10-fold) increase in antibody levels after study treatment. Five of 609 (0.8%; 95% CI, 0.4%-2.8%) evaluable patients developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human thrombin. There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to RECOTHROM applied with absorbable gelatin sponge, USP or with spray applicator.

In a clinical trial comparing RECOTHROM to bovine thrombin (N=411; n=398 antibody evaluable) for the development of specific anti-product antibodies, blood samples were collected at baseline and at Day 29 in both treatment groups and were analyzed by ELISA.1 At baseline, 1.5% of RECOTHROM patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine thrombin patients (n=10/200). Of these patients, none of the RECOTHROM group and eight in the bovine thrombin group exhibited ≥1.0 titer unit (≥10-fold) increases in anti-product antibody levels after study treatment.

At Day 29, three of 198 (1.5%; 95% CI, 0%-4%) patients in the RECOTHROM group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine thrombin group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine thrombin product. Treatment with RECOTHROM resulted in a statistically significant lower incidence of specific anti-product antibody development. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin.

In a trial of patients with a high likelihood of prior exposure to bovine thrombin, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies and 2% of patients (n=4/200) had anti-RECOTHROM product antibodies at baseline.2 Following treatment, none of the 200 evaluable patients (patients for whom post-treatment specimens were available) developed antibodies to RECOTHROM.

In a trial of patients previously exposed to RECOTHROM, 31 patients were re-exposed to
RECOTHROM during a subsequent surgery.3 None of the evaluable patients (n=30) had anti-
RECOTHROM product antibodies at baseline and none developed antibodies at Day 29.

In a trial of RECOTHROM, including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior thrombin exposure had pre-existing anti-RECOTHROM product antibodies at baseline.5 None of the 27 evaluable patients developed anti-RECOTHROM product antibodies at Day 29.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no available data regarding RECOTHROM in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with RECOTHROM thrombin.

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.

8.2 Lactation

Risk Summary
There is no information regarding the presence of RECOTHROM in human milk, the effects 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 RECOTHROM and any potential adverse effects on the breastfed child from RECOTHROM or from underlying maternal condition.

8.4 Pediatric Use

A total of 30 pediatric patients, ages 0 to 16 years (one month to 2 years, n=10; 2 to 12 years, n=12; 12 to 16 years, n=8), were treated in clinical trials with RECOTHROM thrombin using a spray applicator to burn wound excision sites prior to autologous skin grafting. No patient experienced a thromboembolic adverse reaction. The safety of RECOTHROM in pediatric patients greater than or equal to one month of age is supported by these data and by extrapolation of efficacy from adequate and well-controlled studies of RECOTHROM in adults. Safety and efficacy have not been established in neonates [see Adverse Reactions (6)].

8.5 Geriatric Use

Of 644 patients in clinical studies of RECOTHROM thrombin, 36% (n=232/644) were ≥65 years old and 15% (n=95/644) were ≥75 years old.

No differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

RECOTHROM Thrombin topical (Recombinant), is a human coagulation protein produced via

recombinant DNA technology from a genetically modified CHO cell line. RECOTHROM is identical in amino acid sequence and structurally similar to naturally occurring human thrombin. RECOTHROM precursor is secreted to culture medium as single chain form that is proteolytically converted to a two-chain active form (using a protein derived from snakes) and is purified by a chromatographic process that yields a product having hemostatic activities similar to native human thrombin. The cell line used to manufacture RECOTHROM has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of RECOTHROM employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance.

RECOTHROM is provided as a sterile, white to off-white, preservative-free, lyophilized powder in vials for reconstitution with diluent (sterile 0.9% sodium chloride, USP). Reconstitution with the provided diluent, as described [see Dosage and Administration (2.1)] , yields a solution with a pH of 6.0 containing 1000 units/mL of recombinant thrombin for topical use. The formulated product is a clear, colorless solution upon reconstitution and contains the following excipients: histidine, mannitol, sucrose, polyethylene glycol 3350, sodium chloride, and calcium chloride dihydrate, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

RECOTHROM Thrombin topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.

RECOTHROM activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In vitro cytotoxicity studies have been performed in mouse L929 fibroblast cell cultures and
demonstrate a concentration-dependent effect on cell morphology. The thrombin-induced
morphological changes were similar to those seen with bovine thrombin.

13.2 Animal Toxicology and/or Pharmacology

In a study in nonhuman primates, RECOTHROM thrombin was applied directly to a liver wound with an
absorbable gelatin sponge, USP. In a second study, RECOTHROM was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m2. In both studies, RECOTHROM had no effect on clinical signs, serum chemistry, coagulation parameters, or histopathology; only normal postsurgical findings were observed. No animals developed anti-RECOTHROM product antibodies in either study.

RECOTHROM was found to be non-irritating when instilled in the eyes (200 units) or applied to normal or abraded skin of rabbits (up to 1000 units/site).

To evaluate RECOTHROM inhibition and clearance from the bloodstream, radiolabeled
RECOTHROM was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. RECOTHROM did not circulate in the blood as free, active molecule, but was rapidly inactivated (<5 minutes) after formation of complexes with endogenous inhibitors (e.g., antithrombin III); these complexes were cleared by the liver.

RECOTHROM applied with an absorbable gelatin sponge, USP, was shown to decrease time to hemostasis
(TTH) when compared to saline in a rabbit hepatic wound model and rat heminephrectomy model. RECOTHROM also reduced TTH when directly applied in a porcine partial-thickness excisional skin-wound model as compared to saline control (or no treatment).

RECOTHROM applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of RECOTHROM >1000 units/mL were no different than 1000 units/mL while the effect of RECOTHROM diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.

The performance of RECOTHROM mixed with gelatin matrix (FLOSEAL NT Hemostatic Matrix, 5mL) was compared to FLOSEAL Hemostatic Matrix, 5mL (human plasma-derived thrombin mixed with gelatin matrix) in a blinded nonclinical study using a heparinized porcine liver punch model of moderate to severe bleeding. The analysis demonstrated that the performance of RECOTHROM mixed with gelatin matrix was non-inferior to human plasma-derived thrombin mixed with gelatin matrix.

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