Recothrom

Dosage Forms And Strengths

RECOTHROM is available as a sterile lyophilized powder in 5000- and 20,000-unit single-use vials. When reconstituted with the sterile 0.9% sodium chloride, USP provided, the powder yields a solution containing 1000 units/mL of Thrombin topical (Recombinant).

Storage And Handling

RECOTHROM, Thrombin topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:

NDC 28400-105-41 A 5000-unit vial of RECOTHROM with a 5-mL prefilled diluent syringe (containing sterile 0.9% sodium chloride, USP), a sterile needle-free transfer device, a 5-mL sterile empty syringe, and a pre-printed label. 14

NDC 28400-120-41 A 20,000-unit vial of RECOTHROM with a 20-mL vial of diluent (containing sterile 0.9% sodium chloride, USP), 2 sterile needle- free transfer devices, a 20-mL sterile empty syringe, and a pre- printed label.

NDC 28400-120-50 The 20,000-unit RECOTHROM kit co-packaged with the ZymoGenetics Spray Applicator Kit containing a spray pump, a spray bottle, a syringe spray tip, a syringe, a bowl, and 2 blank labels.

No RECOTHROM kit components contain latex.

Store RECOTHROM sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.

Reconstituted solutions of RECOTHROM prepared with sterile 0.9% sodium chloride, USP, may be stored for up to 24 hours at 2°C to 25°C (36°F to 77°F). Discard reconstituted solution after 24 hours.

Manufactured for ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, WA 98102.

Absorption

Bioavailability

Minimally absorbed (<0.37%) following topical application to the liver in a rabbit wound model.11

Onset

Time to hemostasis dependent on concentrations of thrombin and fibrinogen present during clot formation.8 9 15

Elimination

Elimination Route

Rapidly (< 5 minutes) neutralized by endogenous inhibitors in circulation; cleared by liver.1 4 5 6 7 11 12

Recothrom® Thrombin topical (Recombinant), is a topical thrombin indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age.

Recothrom may be used in conjunction with an absorbable gelatin sponge, USP.

Pregnancy

Pregnancy Category C

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

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 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)].

Geriatric Use

Of 644 patients in clinical studies of Recothrom, 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.

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.

Recothrom was evaluated in a randomized, double-blind comparative clinical trial to bovine thrombin. Each thrombin was topically applied to bleeding sites with an absorbable gelatin sponge at a nominal concentration of 1000 units/mL.1 Patients (N=411) were a heterogeneous surgical population undergoing surgery in one of four surgical settings: spinal surgery (n=122, 30%), hepatic resection (n=125, 30%), peripheral arterial bypass surgery (n=88, 21%), and arteriovenous graft formation for hemodialysis access (n=76, 18%). Patients with prior heparin-induced thrombocytopenia were excluded. Patient ages ranged from 21 to 89 years, gender was 53% male and 47% female, and the distribution by race was 68% white, 18% black or African American, and 14% other. The distribution of these characteristics was similar in both the Recothrom and bovine thrombin treatment groups.

The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Recothrom and bovine thrombin in combination with an absorbable gelatin sponge as adjuncts to hemostasis in surgery. Efficacy was evaluated by the incidence of hemostasis within 10 minutes. Bleeding appropriate for evaluation was defined as mild to moderate bleeding, either on its own or remaining after brisk bleeding was controlled by standard surgical modalities. Although multiple bleeding sites could be treated, only one bleeding site per patient was selected to determine effectiveness.

Table 2 summarizes the incidence of hemostasis within 10 minutes for each treatment for the 401 efficacy evaluable patients. The incidence of hemostasis within 10 minutes was comparable for the Recothrom and bovine thrombin groups.

The percentage of patients achieving hemostasis at 1.5, 3, 6, and 10 minutes is listed in Table 3.

1. Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-265.
2. Singla NK, Ballard JL, Moneta G, et al. A phase 3b open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis. J Am Coll Surg. 2009;209(1):68-74.
3. Singla NK, Gasparis AP, Ballard JL, et al. Immunogenicity and safety of re-exposure to recombinant human thrombin in surgical hemostasis. J Am Coll Surg. 2011;213(6):722-727.
4. Greenhalgh DG, Gamelli RL, Collins J, et al. Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting. J Burn Care Res. 2009;30(3):371-379.
5. Foster KN, Mullins RF, Greenhalgh DG, et al. Recombinant human thrombin: safety and immunogenicity in pediatric burn wound excision. J Ped Surg. 2011;46(10):1992-1999.

Recothrom Thrombin topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:

NDC 43825-606-41
A 5000-unit vial of Recothrom with a 5-mL prefilled diluent syringe (containing sterile 0.9% sodium chloride, USP), a sterile needle-free transfer device, a 5-mL sterile empty syringe, and a pre-printed label.

NDC 43825-707-41
A 20,000-unit vial of Recothrom with a 20-mL vial of diluent (containing sterile 0.9% sodium chloride, USP), 2 sterile needle-free transfer devices, a 20-mL sterile empty syringe, and a pre-printed label.

NDC 43825-707-50
The 20,000-unit Recothrom kit co-packaged with Recothrom™ Spray Applicator Kit containing a spray pump, a spray bottle, a syringe spray tip, a syringe, a bowl, and 2 blank labels.

No Recothrom kit components contain latex.

Store Recothrom sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.

Reconstituted solutions of Recothrom prepared with sterile 0.9% sodium chloride, USP, may be stored for up to 24 hours at 2°C to 25°C (36°F to 77°F). Discard reconstituted solution after 24 hours.

• For topical use only. DO NOT INJECT
• Reconstitute Recothrom powder with sterile 0.9% sodium chloride injection, USP, yielding a solution containing 1000 IU/mL.
• Apply Recothrom solution directly to bleeding site surface or in conjunction with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated.