2.1 Reconstitution of RECOTHROM Thrombin

The volume of reconstituted RECOTHROM thrombin required will vary depending on the size and number of bleeding sites to be treated and the method of application.

Inspect the integrity of the RECOTHROM package and contents. Do not use if the packaging or contents have been damaged or opened.

Reconstitute the lyophilized powder using the supplied diluent. Use aseptic technique when handling vials and syringes.

5000-unit RECOTHROM Thrombin Reconstitution

Units used herein represent international units of potency determined using a reference standard that has been calibrated against the World Health Organization Second International Standard for Thrombin.

1.

Remove flip-off cap from the top of the RECOTHROM vial.

2.

Attach the needle-free transfer device and snap it into place on the vial by placing the vial on a flat surface and attaching the transfer device straight into the center of the vial stopper.

3.

Attach the prefilled diluent syringe to the needle-free transfer device.

4.

Inject the 5 mL of diluent from the syringe into the product vial. Keep the syringe plunger depressed.

5.

DO NOT reuse the diluent syringe for transfer of the reconstituted product. Remove and discard the diluent syringe.

6.

Gently swirl and invert the product vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature.

7.

Apply the pre-printed "DO NOT INJECT" label to the sterile, empty transfer syringe provided, then draw up the RECOTHROM solution.

20,000-unit RECOTHROM Thrombin Reconstitution

1.

Remove the flip-off cap from the top of the RECOTHROM vial and the diluent vial.

2.

Attach a needle-free transfer device (one each) to the RECOTHROM and diluent vials and snap them into place by placing the vial on a flat surface and attaching the transfer device straight into the center of the vial stopper.

3.

Open the sterile, empty 20-mL syringe package.

4.

Attach the 20-mL syringe to the needle-free transfer device on the diluent vial (injection of air into the diluent vial may facilitate withdrawal of the diluent).

5.

Draw up 20 mL of diluent from the vial into the syringe.

6.

Remove the diluent-filled syringe from the diluent vial and attach it to the transfer device on the RECOTHROM vial.

7.

Transfer the 20 mL of diluent from the syringe into the RECOTHROM vial; the vacuum in the vial facilitates transfer.

8.

Leave the syringe attached and gently swirl and invert the RECOTHROM vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature.

9.

Apply the pre-printed ‘DO NOT INJECT’ label to the syringe. Draw up the RECOTHROM solution.

2.2 Application Techniques

Topically apply RECOTHROM thrombin solution directly or in conjunction with absorbable gelatin sponge onto the bleeding site. DO NOT INJECT.

The amount required depends upon the area of tissue to be treated and the method of application.

Vials are for single use only. Discard unused contents.

Use with Absorbable Gelatin Sponge

Refer to the absorbable gelatin sponge labeling for safety information and instructions on appropriate use.

1.

Transfer solution from syringe to a sterile bowl or basin.

2.

Place the desired size pieces of the absorbable gelatin sponge into the bowl containing reconstituted RECOTHROM to completely saturate the sponge(s).

3.

Remove the saturated sponge(s) and squeeze gently to remove excess RECOTHROM.

4.

Apply the sponge to the bleeding site in a single layer.

Use with RECOTHROM Thrombin Spray Applicator Kit

1.

Hold the outer sealed tray, peel back the lid, and aseptically transfer the inner sealed sterile tray to the sterile field.

2.

Open the inner tray seal and use the sterile bowl as the receptacle for reconstituted RECOTHROM solution.

3.

Refer to Spray Applicator Kit instructions for spray pump and syringe spray assembly and use.

Use in conjunction with FLOSEAL NT Hemostatic Matrix, 5mL

1.

5000-unit RECOTHROM may be used with FLOSEAL NT Hemostatic Matrix, 5mL according to the FLOSEAL NT Hemostatic Matrix, 5mL instructions for use (IFU).

5.1 Thrombosis

RECOTHROM thrombin may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur.

RECOTHROM thrombin is produced in a genetically modified Chinese Hamster Ovary (CHO) cell line and may contain hamster or snake proteins [see Contraindications (4) and Description (11)].

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 product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical trials have been performed with RECOTHROM thrombin applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to RECOTHROM in these studies.

RECOTHROM Thrombin Used in Conjunction with Absorbable Gelatin Sponge

Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared RECOTHROM to bovine thrombin. Both thrombins were applied with a gelatin sponge in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access.1 The incidence of thromboembolic adverse reactions was similar between the RECOTHROM and bovine thrombin treatment groups (see Table 1).

In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine thrombin within the previous three years were treated with RECOTHROM when undergoing surgeries (spinal, peripheral arterial bypass, or arteriovenous graft formation for hemodialysis access).2 The incidence of thromboembolic adverse reactions in this study was 9%.

In an open-label, single-group trial of re-exposure to RECOTHROM (N=31), patients with documented prior exposure to RECOTHROM were treated with RECOTHROM during surgery (spinal, peripheral arterial bypass, arteriovenous graft formation, or other procedures).3 The incidence of thromboembolic adverse reactions in this study was 3%.

In other randomized, double-blind trials across a range of surgical settings (N=130; spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the safety of RECOTHROM (n=88 patients) was compared to placebo (RECOTHROM excipients reconstituted with sterile 0.9% sodium chloride, USP) (n=42 patients). The incidence of thromboembolic adverse reactions in this study was 5% for RECOTHROM and 12% for placebo.

RECOTHROM Thrombin Applied with Spray Applicator

RECOTHROM was applied with a spray applicator in two open-label clinical trials: a single-group trial in adult and pediatric burn patients (N=72; ≤16 years of age, (n=4) and ≥17 years of age, (n=68)) treated with RECOTHROM applied to the wound excision site prior to autologous skin grafting4; and in a single-group trial in pediatric patients (one month to 17 years of age) undergoing synchronous burn wound excision and autologous skin grafting (N=30; ≤16 years of age, (n=26); ≥17 years of age, (n=4)).5 In the first study, the incidence of thromboembolic adverse reactions was 1%. In the second study, there were no reported thromboembolic adverse reactions [see Use in Specific Populations (8.4)].

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.

8.1 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.

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.

13.1 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.