DRUGS & SUPPLEMENTS
Active ingredient: Thrombin Human
Thrombin Human uses
1 INDICATIONS AND USAGE
Thrombin Human ®, Thrombin Human topical (Recombinant), is a topical Thrombin Human 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.
Thrombin Human may be used in conjunction with an absorbable gelatin sponge, USP.
Thrombin Human, Thrombin Human topical (Recombinant), is a topical Thrombin Human 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. (1)
Thrombin Human may be used in conjunction with an absorbable gelatin sponge, USP. (1)
2 DOSAGE AND ADMINISTRATION
For topical use only. DO NOT INJECT.
2.1 Reconstitution of Thrombin Human
The volume of reconstituted Thrombin Human 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 Thrombin Human 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 Thrombin Human 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 Human.
20,000-unit Thrombin Human Reconstitution
2.2 Application Techniques
Topically apply Thrombin Human 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.
Use with ZymoGenetics Spray Applicator Kit
3 DOSAGE FORMS AND STRENGTHS
Thrombin Human 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 Human topical (Recombinant).
Thrombin Human is available as 5000-unit and 20,000-unit vials of sterile recombinant topical Thrombin Human lyophilized powder for solution. When reconstituted as directed, the final solution contains 1000 units/mL of Thrombin Human. (3)
5 WARNINGS AND PRECAUTIONS
Thrombin Human may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.
5.2 Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, may occur. Thrombin Human 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 ADVERSE REACTIONS
Thromboembolic adverse reactions were reported in 6% of surgical patients treated with Thrombin Human in all completed clinical trials [see Warnings and Precautions (5.1) ].
Antibody formation to Thrombin Human occurred in <1% of patients. None of the antibodies detected neutralized native human Thrombin Human [see Adverse Reactions (6.2) ].
To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-888-784-7662 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 Thrombin Human applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to Thrombin Human in these studies.
Thrombin Human Used in Conjunction with Absorbable Gelatin Sponge
Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared Thrombin Human to bovine Thrombin Human. 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 Thrombin Human and bovine Thrombin Human treatment groups.
In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine Thrombin Human within the previous three years were treated with Thrombin Human 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 Thrombin Human (N=31), patients with documented prior exposure to Thrombin Human were treated with Thrombin Human 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 Thrombin Human (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 Thrombin Human and 12% for placebo.
Thrombin Human Applied with Spray Applicator
Thrombin Human 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 Thrombin Human 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) ].
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 Thrombin Human was evaluated in multiple clinical trials and included patients with a single exposure to Thrombin Human as well as patients who were re-exposed to Thrombin Human 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 Human. There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to Thrombin Human applied with absorbable gelatin sponge, USP or with spray applicator.
In a clinical trial comparing Thrombin Human to bovine Thrombin Human (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 Thrombin Human patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine Thrombin Human patients (n=10/200). Of these patients, none of the Thrombin Human group and eight in the bovine Thrombin Human 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 Thrombin Human group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine Thrombin Human group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine Thrombin Human product. Treatment with Thrombin Human 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 Thrombin Human group neutralized native human Thrombin Human. Antibodies against bovine Thrombin Human product were not tested for neutralization of native human Thrombin Human.
In a trial of patients with a high likelihood of prior exposure to bovine Thrombin Human, 15.6% of patients (n=32/205) had anti-bovine Thrombin Human 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 Thrombin Human.
In a trial of patients previously exposed to Thrombin Human, 31 patients were re-exposed to Thrombin Human 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 Thrombin Human, including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior Thrombin Human 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
Pregnancy: No human or animal data. Use only if clearly needed.
Pregnancy Category C
Animal reproduction studies have not been conducted with Thrombin Human. It is also not known whether Thrombin Human can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Thrombin Human should be given to a pregnant woman only if clearly needed.
8.4 Pediatric Use
A total of 30 pediatric patients, ages 0 to 16 years, were treated in clinical trials with Thrombin Human using a spray applicator to burn wound excision sites prior to autologous skin grafting. No patient experienced a thromboembolic adverse reaction. The safety of Thrombin Human 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 Thrombin Human 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 Thrombin Human, 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.
Thrombin Human, Thrombin Human topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Thrombin Human is identical in amino acid sequence and structurally similar to naturally occurring human Thrombin Human. Thrombin Human 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 Human. The cell line used to manufacture Thrombin Human has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Thrombin Human employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance.
Thrombin Human 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 Human 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
Thrombin Human, Thrombin Human topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.
Thrombin Human 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 Human.
13.2 Animal Toxicology and/or Pharmacology
In a study in nonhuman primates, Thrombin Human was applied directly to a liver wound with an absorbable gelatin sponge, USP. In a second study, Thrombin Human was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m2. In both studies, Thrombin Human 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.
Thrombin Human 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 Thrombin Human inhibition and clearance from the bloodstream, radiolabeled Thrombin Human was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. Thrombin Human 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.
Thrombin Human 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. Thrombin Human also reduced TTH when directly applied in a porcine partial-thickness excisional skin-wound model as compared to saline control (or no treatment).
Thrombin Human applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of Thrombin Human >1000 units/mL were no different than 1000 units/mL while the effect of Thrombin Human diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.
14 CLINICAL STUDIES
Thrombin Human was evaluated in a randomized, double-blind comparative clinical trial to bovine Thrombin Human. Each Thrombin Human 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 Thrombin Human and bovine Thrombin Human treatment groups.
The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Thrombin Human and bovine Thrombin Human 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 Thrombin Human and bovine Thrombin Human groups.
The percentage of patients achieving hemostasis at 1.5, 3, 6, and 10 minutes is listed in Table 3.
16 HOW SUPPLIED/STORAGE AND HANDLING
Thrombin Human, Thrombin Human topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:
A 5000-unit vial of Thrombin Human 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.
A 20,000-unit vial of Thrombin Human 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.
The 20,000-unit Thrombin Human kit co-packaged with The Medicines Company Spray Applicator Kit containing a spray pump, a spray bottle, a syringe spray tip, a syringe, a bowl, and 2 blank labels.
No Thrombin Human kit components contain latex.
Store Thrombin Human sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.
Reconstituted solutions of Thrombin Human 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.
17 PATIENT COUNSELING INFORMATION
Because topical Thrombin Human may cause the formation of clots in blood vessels if absorbed systemically, advise patients to consult their physician if they experience leg tenderness or swelling, chest pain, shortness of breath, or difficulty speaking or swallowing [see Warnings and Precautions (5.1) ].
Manufactured for The Medicines Company
The Medicines Company, 8 Sylvan Way, Parsippany NJ 07054
U.S. License No. 1902
Thrombin Human is a registered trademark of ZymoGenetics, Inc. All other trademarks are the property of their respective owners.
[PN 6001- 1 PI; Rev March 2014]
PRINCIPAL DISPLAY PANEL - 5000-UNIT VIAL
FOR TOPICAL USE ONLY - DO NOT INJECT
Thrombin Human, TOPICAL
5,000 units NDC: 65293-006-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Thrombin Human, TOPICAL (RECOMBINANT) 5,000 units
PRINCIPAL DISPLAY PANEL - 20000-UNIT VIAL
FOR TOPICAL USE ONLY - DO NOT INJECT
Thrombin Human, TOPICAL
20,000 units NDC: 65293-007-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Thrombin Human, TOPICAL (RECOMBINANT) 20,000 units
Thrombin Human available forms, composition, doses:
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Frequently asked QuestionsCan i drive or operate heavy machine after consuming Thrombin Human?
Depending on the reaction of the Thrombin Human after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Thrombin Human not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Thrombin Human addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Thrombin Human, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Thrombin Human consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
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The information was verified by Dr. Arunabha Ray, MD Pharmacology