Drug Detail:Thrombin alfa (recombinant) (topical) (monograph) (Recothrom)
Drug Class:
Highlights of Prescribing Information
EVITHROM® [Thrombin, Topical (Human)]
Lyophilized Powder for Solution
For topical use
Initial U.S. Approval: 2007
Indications and Usage for Thrombin Human
- EVITHROM® is a topical thrombin indicated as an aid to 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 (1).
- EVITHROM® may be used in conjunction with an Absorbable Gelatin Sponge, USP (1).
Thrombin Human Dosage and Administration
- For topical use only. DO NOT INJECT (2.2).
- Apply EVITHROM® on the surface of bleeding tissue only.
- The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. In clinical studies, volumes up to 10 ml were used in conjunction with Absorbable Gelatin Sponge, USP (2.2).
Dosage Forms and Strengths
EVITHROM® is a lyophilized powder for solution containing 2000 (1600-2400) units of human thrombin. After reconstituted the final solution contains 1000 (800-1200) units/ml of EVITHROM® (3).
Contraindications
- Do not use in individuals known to have an anaphylactic or severe systemic reaction to EVITHROM® or to human blood products (4).
- Do not use for treatment of severe or brisk arterial bleeding (4).
Warnings and Precautions
- Potential risk of thrombosis if absorbed systemically (5.1).
- May carry a risk of transmitting infectious agents such as viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite manufacturing steps designed to reduce the risk of viral transmission (5.2).
- Hypersensitivity reactions, including anaphylaxis, may occur (5.1).
Adverse Reactions/Side Effects
- The most common adverse reactions (incidence 2%) were prolonged activated partial thromboplastin time, increased INR, decreased lymphocyte count, prolonged prothrombin time and increased neutrophil count (6).
- None of the patients treated with EVITHROM® developed antibodies to human thrombin or to human Factor V/Va. The clinical significance of these findings is unknown (6).
To report SUSPECTED ADVERSE REACTIONS, contact ETHICON Customer Support Center at (877) 384-4266 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Use In Specific Populations
Animal Reproduction studies have not been conducted with EVITHROM®. EVITHROM® should only be used in pregnancy if clearly indicated (8.1).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 11/2020
Full Prescribing Information
1. Indications and Usage for Thrombin Human
EVITHROM® Thrombin, Topical (Human), is indicated as an aid to 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.
EVITHROM® Thrombin, Topical (Human), may be used in conjunction with an Absorbable Gelatin Sponge, USP.
2. Thrombin Human Dosage and Administration
2.1 Dose
For Topical Use Only. DO NOT INJECT.
The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. As an approximate guide, volumes up to 10 ml were used in clinical studies where EVITHROM® was used in conjunction with Absorbable Gelatin Sponge, USP.
2.2 Preparation
- Use aseptic technique when handling vials and syringes.
- Remove the flip-off plastic cap from the vial to expose the rubber stopper.
- Reconstitute the lyophilized human thrombin powder with 2 ml of sterile Water for Injection, USP using the provided reconstitution device.
- Shake gently until the solution is clear.
- Reconstituted solution is stable for up to 8 hours at room temperature and should be used within this time period.
3. Dosage Forms and Strengths
EVITHROM® is a sterile lyophilized powder for solution 2000 (1600-2400) units of lyophilized human thrombin powder for reconstitution. After reconstituted, the final solution contains 1000 (800-1200) units/ml of human thrombin.
Potency, expressed in units, is determined using a clotting assay against an internal reference standard for potency that has been calibrated against the World Health Organisation (WHO) Second International Standard for Thrombin, 01/580. Therefore, a unit used herein is equivalent to an International Unit.
4. Contraindications
- Do not use in individuals known to have an anaphylactic or severe systemic reaction to EVITHROM® or to human blood products.
- Do not use for the treatment of severe or brisk arterial bleeding.
5. Warnings and Precautions
5.2 Anaphylactic/Hypersensitivity Reactions
Anaphylactic reactions may occur in rare cases. No adverse events of this type were reported during the conduct of the clinical trials. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.
5.3 Transmission of Infectious Agents
Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections and by inactivating and removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products.
6. Adverse Reactions/Side Effects
The most common adverse reactions during clinical trial (reported in at least 2% of subjects treated with EVITHROM®) were prolonged activated partial thromboplastin time, increased INR, decreased lymphocyte count, prolonged prothrombin time and increased neutrophil count.
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.
In a multicenter, prospective, controlled, randomized, double-blinded clinical trial of 305 subjects where EVITHROM® (n=153) was compared with bovine thrombin (n=152), occurrence of adverse events was not statistically different between the two groups.
Overall, adverse events occurred in similar proportions of subjects in the two groups (see Table 1). No clinically significant differences were seen in age (<65 years, >65 years) or gender subgroup analyses of adverse events.
At least one serious adverse event (SAE) was reported for 26/153 (17%) subjects treated with human thrombin and 17/152 (11%) subjects treated with bovine thrombin. The SAEs reported were associated with post-surgical complications (e.g. wound infection 3/153 for EVITHROM® and 2/152 for bovine thrombin) and the medical condition of the subject and were not considered related to study drug. Two subjects (1.3%) in EVITHROM® group experienced a treatment emergent severe adverse event: respiratory arrest and post-procedural hematoma (in one subject) and extradural hematoma. Three subjects in the bovine thrombin group experienced a treatment emergent severe adverse event: hyperhidrosis, pyrexia and post-procedural hematoma.
No deaths were reported during the study period.
Viral serology was not monitored during the trial with EVITHROM®. However, no adverse events indicative of infection with transfusion-transmissible agents were reported.
| Thrombin Type | |||
|---|---|---|---|
| System Organ Class/Adverse Event | EVITHROM®
(n=153) | Bovine (n=152) | Total (n=305) |
| Investigations | 11 (7.2%) | 14 (9.2%) | 25 (8.2%) |
| Activated partial thromboplastin time increased | 4 (2.6%) | 8 (5.3%) | 12 (3.9%) |
| International normalized ratio increased | 4 (2.6%) | 5 (3.3%) | 9 (3.0%) |
| Lymphocyte count decreased | 4 (2.6%) | 2 (1.3%) | 6 (2.0%) |
| Prothrombin time prolonged | 4 (2.6%) | 8 (5.3%) | 12 (3.9%) |
| Neutrophil count increased | 3 (2.0%) | 2 (1.3%) | 5 (1.6%) |
| Skin and Subcutaneous Tissue Disorders | 1 (0.7%) | 3 (2.0%) | 4 (1.3%) |
| Pruritus | 1 (0.7%) | 3 (2.0%) | 4 (1.3%) |
| General Disorders and Administration Site Conditions | 0 | 3 (2.0%) | 3 (1.0%) |
8. Use In Specific Populations
8.4 Pediatric Use
Of the 155 patients undergoing liver surgery who were treated in adequate and well-controlled studies of EVICEL® Fibrin Sealant (Human), in which EVITHROM® is a component, eight were pediatric patients. Of these, five were less than 2 years old and three were between 2 and 12 years old. Use of EVITHROM® in pediatric patients is supported by these data and by extrapolation of findings for safety and efficacy in adults.
11. Thrombin Human Description
EVITHROM® is a sterile lyophilized powder of purified human thrombin (1600-2400 units) of white to slightly yellowish color. When reconstituted, EVITHROM® solution, pH 6.8-7.2, is clear to slightly opalescent and colorless to slightly yellowish. Other inactive ingredients are Calcium chloride, Human albumin, Mannitol, Sodium acetate
EVITHROM® is made from pooled Human Source obtained from US licensed plasma collection centers. Individual plasma units obtained for production of EVITHROM® are tested by licensed serological tests for HBsAg, HIV 1 & 2 Ab and HCV Ab. Additionally, the plasma units are tested by licensed Nucleic Acid Testing (NAT) for HIV-1, HCV, HBV, HAV and parvovirus B19. All tests for HIV, HCV, HBV and HAV must be negative (non-reactive). However, since the effectiveness of the HBV and HAV NAT methods in detecting low levels of viral material is still under investigation, the significance of a negative result for these viruses is unknown. The level of parvovirus B19 contamination is not permitted to exceed 10,000 copies/ml. This limit is applied to restrict the viral load of parvovirus B19 in the starting plasma pool. In addition to the screening of plasma units, each manufacturing pool is tested for HBsAg, HIV-1 & 2 Ab, HCV NAT and for parvovirus B19 by NAT. Manufacturing pool testing, however, is of lower sensitivity than individual unit testing.
EVITHROM® is manufactured by purification of prothrombin from cryo-poor plasma followed by activation with calcium chloride, or alternatively with calcium chloride in combination with Gluconate. The manufacturing process includes two targeted steps for inactivation or removal of viruses. The first of these is treatment with a solvent/detergent (S/D) mixture (1% tri-n-butyl phosphate and 1% Triton X-100 or 1% Polysorbate-80 and 0.3% tri-n-butyl phosphate) for 6 hours at 26°C to inactivate lipid enveloped viruses. The S/D reagents are removed by cation exchange chromatography. Mannitol and human albumin are used to stabilize the solution, which undergoes nanofiltration for removal of both enveloped and non-enveloped viruses. After nanofiltration, the solution is formulated with calcium chloride, sterile filtered and aseptically filled and frozen.
The effectiveness of the S/D treatment and nanofiltration procedures for reducing virus content has been assessed using a series of viruses with a range of physico-chemical characteristics. The results of the validation studies are summarized in Table 2.
| Virus | HIV-1 | BVDV | PRV | EMCV | HAV | MVM | PPV |
|---|---|---|---|---|---|---|---|
| Reduction factor (log10) | |||||||
| HIV-1: Human Immunodeficiency Virus Type 1; | |||||||
| BVDV: Bovine Viral Diarrhea Virus; | |||||||
| PRV: Pseudorabies Virus; | |||||||
| EMCV: Encephalomyocarditis Virus; | |||||||
| HAV: Hepatitis A Virus; | |||||||
| MVM: Minute Virus of Mouse; | |||||||
| PPV: Porcine Parvovirus | |||||||
| SD Treatment | ≥5.5 | >4.6 | >4.2 | Not Done | Not Done | Not Done | Not Done |
| Nanofiltration | ≥4.6 | ≥5.6 | ≥5.7 | ≥7.4 | ≥7.5 | ≥6.3 | ≥ 5.6 |
| Global Reduction Factor | ≥10.1 | ≥10.2 | ≥9.9 | ≥7.4
| ≥7.5
| ≥6.3 | ≥5.6 |
12. Thrombin Human - Clinical Pharmacology
EVITHROM® requires no intermediate physiological agent because it clots the fibrinogen of the blood directly. Failure to clot blood occurs in the rare case where the primary clotting defect is the absence of fibrinogen itself. The speed with which thrombin clots blood is dependent upon the concentration of both thrombin and fibrinogen.
12.1 Mechanism of Action
Thrombin (coagulation Factor IIa) is a highly specific protease that transforms plasma fibrinogen into fibrin which, in the presence of Factor XIII in the patient's plasma, is cross-linked to form a stable clot. When applied to a surgical wound where bleeding is present, thrombin activates fibrinogen in the patient's plasma to form fibrin, which results in clot formation and hemostasis. The fibrin clot is stabilized by cross-linking occurring as a result of activation of the patient's endogenous Factor XIII, which requires the presence of calcium.
13. Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of EVITHROM® due to the human origin of thrombin.
Studies were performed in bacteria to determine mutagenicity of human thrombin alone, and solvent/detergent residues [tri-n-butyl phosphate (TnBP) and Triton X-100], used in the virus inactivation manufacturing step. These studies were negative for both thrombin and for TnBP or Triton X-100 at all concentrations tested. All concentrations of the combination of TnBP and Triton X-100 also tested negative in assays performed to determine mammalian cell mutagenicity, chromosomal aberrations and micronuclei induction. No study was performed for Polysorbate-80 and tri-n-butyl phosphate.
The effect of EVITHROM® on fertility has not been evaluated. Reproductive studies were performed in rats with the combination of solvent detergent impurities, TnBP and Triton X-100 at doses up to approximately 600-fold human dose of TnBP (900 µg/kg/day) and 3000-fold human dose of Triton X-100 (4500 µg/kg/day) resulted in increased post-implantation loss and an increased number of late resorptions. Other studies performed with combinations of TnBP (300-fold human dose, 450 µg/kg/day) and Triton X-100 (1500-fold human dose, 2250 µg/kg/day) resulted in increased resorption rates, decreased fetal body weights, and an increased number of runts. No embryo-fetal adverse effects were observed at doses up to 300 µg/kg/day TnBP and 1500 µg/kg/day Triton X-100, 200-fold and 1000-fold the human dose, respectively.
13.2 Animal Toxicology and/or Pharmacology
EVICEL Fibrin Sealant (Human), which includes EVITHROM® as one of the active components, was classified as non-irritant in the Primary Cutaneous Irritation Test and slightly irritant in the Ocular Irritation test.
Neurotoxicity studies performed with EVITHROM® or with EVICEL confirmed that intracerebral application of thrombin was not associated with any evidence of neurotoxicity.
No toxicological effects due to solvent/detergent reagents [tri-n-butyl phosphate (TnBP) and Triton X-100] used in the virus inactivation procedure are expected since the residual levels are less than 5 µg/ml. This evaluation was not performed for Polysorbate-80.
14. Clinical Studies
EVITHROM® was compared with bovine thrombin in a multicenter, prospective, randomized, controlled, double-blinded clinical trial of 305 subjects at 22 centers in the US. Subjects undergoing elective cardiovascular, neurologic (spinal) or general surgical procedures were randomized (stratified by surgical specialty) when there was oozing or bleeding of mild intensity that could not be controlled by other surgical techniques and the surgeon determined that a topical hemostatic agent was necessary. Bovine thrombin and EVITHROM® were applied with SURGIFOAM® Absorbable Gelatin Sponge, USP.
Treatment with EVITHROM® was comparable to treatment with bovine thrombin in achieving hemostasis within:
- 10 minutes of product application and
- 6 and 3 minutes of product application.
| Time Interval | Treatment Group: # Successes/N (%) | Ratio Human/Bovine | 95% CI for Ratio Human/Bovine*,† |
|
|---|---|---|---|---|
| EVITHROM®
N=153 | Bovine thrombin N=152 |
|||
|
||||
| 10 minutes | 149/153 (97.4) | 148/152 (97.4) | 1.00 | 0.96, 1.05 |
| 6 minutes | 145/153 (94.8) | 141/152 (92.8) | 1.02 | 0.96, 1.09 |
| 3 minutes | 112/153 (73.2) | 110/152 (72.4) | 1.01 | 0.88, 1.16 |
| Surgical Specialty | Treatment Group: # Successes/N (%) | Ratio Human/Bovine | 95% CI for Ratio Human/Bovine*,† |
|
|---|---|---|---|---|
| EVITHROM® | Bovine thrombin | |||
|
||||
| Cardiovascular | 44/47 (93.6) | 38/46 (82.6) | 1.13 | 0.97, 1.36 |
| Neurosurgical (Spine) | 60/61 (98.4) | 59/60 (98.3) | 1.00 | 0.93, 1.08 |
| General Surgery | 41/45 (91.1) | 44/46 (95.7) | 0.95 | 0.82, 1.08 |
| Overall | 145/153 (94.8) | 141/152 (92.8) | 1.02 | 0.96, 1.09 |
At the 6 minute and 10 minute time points, >90% of subjects from all surgeries in both study groups had achieved hemostasis. The following results were documented for the 3 minute time point as stratified by surgery and study treatment: (1) cardiovascular surgery - human thrombin: 61.7%; bovine thrombin: 63.0%, (2) spinal surgery - human thrombin: 83.6%; bovine thrombin: 80.0%, (3) general surgery - human thrombin: 71.1%; bovine thrombin: 71.7% for an overall ratio of proportions of 1.01.
16. How is Thrombin Human supplied
EVITHROM® is supplied in a single-use 2 ml vial containing 2000 (1600-2400) units of lyophilized human thrombin powder for reconstitution in 2 ml Water for Injection, USP.
NDC 63713-461-02
17. Patient Counseling Information
Inform patients of the following:
- Some viruses such as hepatitis A virus and parvovirus B19 are particularly difficult to remove or inactivate. Parvovirus B19 most seriously affects pregnant women or immune-compromised individuals. Symptoms of parvovirus B19 infection include: fever, drowsiness, chills and runny nose followed about two weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, fatigue and low-grade fever followed by nausea, vomiting and abdominal pain. Dark urine and a yellowed complexion are also common symptoms. Consult your physician if such symptoms appear.
- If absorbed systemically EVITHROM® could potentially cause blood clotting disorders. Consult your physician if leg tenderness or swelling, chest pain, or shortness of breath appears.
| THROMBIN HUMAN
thrombin human powder, for solution |
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| Labeler - Ethicon, Inc (002144145) |
| Registrant - Omrix Biopharmaceuticals Ltd (514577949) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Omrix Biopharmaceuticals Ltd | 514577949 | analysis, api manufacture, manufacture, label, pack | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Patheon Italia S.p.A. | 434078638 | manufacture, analysis, label, pack | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Instituto Grifols S.A. | 465562213 | MANUFACTURE | |
