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.

For topical use only. DO NOT INJECT.

Do not inject RECOTHROM directly into the bloodstream. Intravascular injection of thrombin-containing hemostats may result in life-threatening intravascular coagulation or death.

RECOTHROM is for topical use only.

Apply on the surface of bleeding tissue only.

The volume of reconstituted RECOTHROM required will vary, depending on the size and number of bleeding sites to be treated and the method of application. The healthcare professional should determine the number of vials required to produce a sufficient volume of reconstituted product. The mean volume of RECOTHROM used in the pivotal phase III trial was 11.6 mL.

Administration

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.

20,000 IU 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 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.

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.

4.4.1    Thrombosis

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

4.4.2    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 (2) and (4)].

Interactions with other drugs, food, herbal preparations, or laboratory tests have not been established.

4.6.1    Pregnancy

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

4.6.2    Lactation

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.

Not relevant

Thromboembolic adverse reactions were reported in 6% of surgical patients treated with RECOTHROM thrombin in all completed clinical trials (N=644) [see 4.4].

Antibody formation to RECOTHROM occurred in <1% of patients. None of the antibodies detected neutralized native human thrombin [see 4.8.2].

4.8.1    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). 

Table 1: Incidence of Adverse Reactions with RECOTHROM Thrombin and Bovine Thrombin

*THROMBIN-JMI Thrombin, Topical (Bovine)

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 (4.8.2)].

4.8.2   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.

Pediatric population

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.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

·   Saudi Arabia:

·   Other GCC States:

A maximum dose of topically applied RECOTHROM has not been established. In clinical studies, the maximum volume administered was 48 mL.

Local hemostatics group, thrombin

ATC code: B02BD30

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.

RECOTHROM was evaluated in a Phase III study conducted in 411 subjects undergoing surgery in 1 of 4 surgical settings: spinal surgery, hepatic segment surgery, peripheral arterial bypass surgery, and arteriovenous graft formation for hemodialysis access. The study was a multiple site, randomized, double-blind, controlled evaluation of RECOTHROM compared to bovine thrombin, each at a nominal concentration of 1000 IU/mL topically applied to bleeding sites with an absorbable gelatin sponge.

Not applicable.

RECOTHROM is intended for topical use only. Intravascular administration is contraindicated (see 4.3 section). As a consequence, intravascular pharmacokinetic studies were not performed in humans.

5.3.1    Nonclinical Toxicology

5.3.1.1 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.

5.3.1.2 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.

5.3.2   Clinical Studies

RECOTHROM thrombin 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.

Table 2: Hemostasis Within 10 Minutes*

*Evaluation of hemostasis at ≤ 10 minutes for patients treated at 1 of 4 primary TTH bleeding site types: epidural venous plexus, hepatic resection site, peripheral arterial bypass proximal anastomosis, and arteriovenous graft arterial anastomosis.

^†THROMBIN-JMI Thrombin, Topical (Bovine)

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

Table 3: Cumulative Incidence of Hemostasis Over Time

*THROMBIN-JMI Thrombin, Topical (Bovine)

5.3.3   References

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.

Histidine, Mannitol, Sucrose, Sodium chloride, Polyethylene glycol 3350, Calcium chloride dihydrate

Not applicable

Store at 2°C to 25°C.

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.

Discard reconstituted solution after 24 hours.

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

A 20,000 IU vial (20-mL) 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.

No RECOTHROM kit components contain latex.

See under section 4.2, Posology and Method of Administration.