TISSEEL FROZEN- fibrinogen human and thrombin human solution
TISSEEL- fibrinogen human and thrombin human
Baxalta US Inc.
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use TISSEEL safely and effectively. See full prescribing information for TISSEEL.
TISSEEL [Fibrin Sealant] For Topical Use Only Frozen solution and lyophilized powder for solution for topical application Initial U.S. Approval: 1998 RECENT MAJOR CHANGESAdverse Reactions; Post Marketing (6.3) 11/2009 INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATIONFor Topical Use Only. Do Not Inject (2) TISSEEL Kit (Freeze-Dried) requires reconstitution prior to use (2.1) TISSEEL Pre-filled Syringe (Frozen) requires thawing prior to use (2.2) Apply TISSEEL as a thin layer (2.3, 5.2) Vials and pre-filled syringes are for single use only. Discard unused contents (2.3) To ensure adequate mixing, expel and discard the first several drops from the cannula in cases where very small volumes (1-2 drops) are applied (2.3) DOSAGE FORMS AND STRENGTHSCONTRAINDICATIONSWARNINGS AND PRECAUTIONS
ADVERSE REACTIONSDRUG INTERACTIONSOxycellulose containing preparations may reduce the efficacy of TISSEEL and should not be used as carrier materials (7) See 17 for PATIENT COUNSELING INFORMATION. Revised: 9/2009 |
TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in surgeries involving cardiopulmonary bypass and treatment of blunt or penetrating splenic injuries when control of bleeding by conventional surgical techniques, including suture, ligature, and cautery, is ineffective or impractical. TISSEEL is a hemostatic agent that may be used in fully heparinized patients undergoing cardiopulmonary bypass.
FOR TOPICAL USE ONLY – DO NOT INJECT.
The required dose of TISSEEL depends on the size of the surface to be covered. The approximate surface areas covered by each package size of TISSEEL are listed in the following table:
Maximum size of the area to be sealed using cannula | Maximum size of the area to be sealed using compressed gas | Required package size of TISSEEL |
8 cm2 | 100 cm2 | 2 mL |
16 cm2 | 200 cm2 | 4 mL |
40 cm2 | 500 cm2 | 10 mL |
It is recommended that every time a patient receives a dose of TISSEEL, the name and batch number of the product are documented in order to maintain a record of the batches used.
During preparation of TISSEEL Kit:
DO NOT EXPOSE TO TEMPERATURES ABOVE 37°C
DO NOT MICROWAVE
DO NOT REFRIGERATE OR FREEZE AFTER RECONSTITUTION
Do not use iodine or heavy metal containing preparations such as betadine for disinfection of vial stoppers. Allow alcohol-based disinfectants to evaporate before puncturing stopper.
Use separate syringes for reconstituting Sealer Protein and Thrombin solutions and for application to prevent premature clotting.
After reconstitution, the product must be used within 4 hours.
TISSEEL Kit contains the following substances in four separate vials:
-Sealer Protein Concentrate (Human)
-Fibrinolysis Inhibitor Solution (Synthetic)
-Thrombin (Human)
-Calcium Chloride Solution
Freeze-dried Sealer Protein Concentrate and Thrombin are reconstituted in Fibrinolysis Inhibitor Solution and Calcium Chloride Solution, respectively. The Sealer Protein Solution and Thrombin Solution are then combined using the DUPLOJECT Preparation and Application System, or an equivalent delivery device cleared by FDA for use with TISSEEL, to form the Fibrin Sealant.
Prewarming TISSEEL Kit with FIBRINOTHERM
If a FIBRINOTHERM device is not available, contact Baxter (1-800-423-2090) for assistance. See FIBRINOTHERM manual for complete operating instructions.
Preparation of Sealer Protein Solution with FIBRINOTHERM
Notes:
-Do not use the Sealer Protein Concentrate until it has fully dissolved. If the Sealer Protein Concentrate has not dissolved within 20 minutes using the FIBRINOTHERM device, discard the vial and prepare a fresh kit.
-If not used promptly, keep the Sealer Protein Solution at 37°C without stirring. To ensure homogeneity, switch on the stirrer of the FIBRINOTHERM device shortly before drawing up the solution.
Preparation of Thrombin Solution with FIBRINOTHERM
Transferring to the Sterile Field
For transfer of the Sealer Protein Solution and the Thrombin Solution to the sterile field, the scrub nurse should withdraw the solutions while the circulating nurse holds the non-sterile vials. The solutions should be withdrawn slowly by firm constant aspiration to reduce the risk of large air bubbles.
During preparation of TISSEEL (frozen):
DO NOT EXPOSE TO TEMPERATURES ABOVE 37°C
DO NOT MICROWAVE
DO NOT REFRIGERATE OR RE-FREEZE
Do not use TISSEEL (frozen) until it is completely thawed and warmed (liquid consistency).
Do not remove the protective syringe cap until use.
TISSEEL (frozen) can be prepared (thawed) using one of two options:
Room Temperature Thawing
Unopened pouches may be stored for up to 48 hours at room temperature (15-25°C).
When product is thawed at room temperature, warm to 33-37°C prior to use and use immediately. The total thawing and warming time cannot exceed 48 hours.
Quick Thawing
Option 1 – Thawing on the sterile field using a water bath
33°C to 37°C sterile water bath - transfer DUO set and the inner pouch to the sterile field, remove pre-filled syringe from inner pouch and place directly into sterile water bath. Ensure the contents of the pre-filled syringe are completely immersed under the water.
Approximate thawing and warming times when using this method are:
Pack Size | Thawing/Warming Times 33°C to 37°C Sterile Water Bath (Pouches Removed) |
2 mL | 5 minutes |
4 mL | 5 minutes |
10 mL | 12 minutes |
Option 2 – Thawing off the sterile field using a water bath
33°C to 37°C non-sterile water bath in two pouches - maintain the pre-filled syringe in both pouches and place into a water bath off the sterile field for appropriate time. Ensure the pouches remain submerged throughout thawing. Remove from the water bath after thawing, dry external pouch and transfer inner pouch with pre-filled syringe onto the sterile field.
Approximate thawing and warming times when using this method are:
Pack Size | Thawing/Warming Times 33°C to 37°C Non-Sterile Water Bath (In Pouches) |
2 mL | 30 minutes |
4 mL | 40 minutes |
10 mL | 80 minutes |
Option 3 – Thawing off the sterile field using an incubator
33°C to 37°C incubator in pouches – maintain the pre-filled syringe in both pouches and place into an incubator for appropriate time. Remove from incubator after thawing and transfer inner pouch with pre-filled syringe onto the sterile field.
Approximate thawing and warming times when using this method are:
Pack Size | Thawing/Warming Times 33°C to 37°C Incubator (In Pouches) |
2 mL | 40 minutes |
4 mL | 85 minutes |
10 mL | 105 minutes |
Maintain the product at 33-37°C until use. If the package is opened or warmed to 33-37°C it must be used within 4 hours.
Vials and pre-filled syringes are for single use only. Discard any unused product.
The wound surface should be as dry as possible before application.
Avoid application beyond the intended area.
Immediately before application, expel and discard the first several drops from the application cannula to ensure adequate mixing of the Sealer Protein and Thrombin solutions in cases where very small volumes (1-2 drops) of product are administered.
To prevent adherence, wet gloves with normal saline before product contact.
Apply TISSEEL as a thin layer. The initial amount of the product to be applied should be sufficient to entirely cover the intended application area. The application can be repeated, if necessary. If repeat application is necessary, reapply before polymerization takes place since TISSEEL may not adhere to a polymerized layer.
After the two components have been applied, fix or hold the sealed parts in the desired position for at least three to five minutes to ensure the setting TISSEEL adheres firmly to the surrounding tissue.
TISSEEL Kit (Freeze-Dried)
Apply TISSEEL using the DUPLOJECT Fibrin Sealant Preparation and Application System or an equivalent delivery device cleared by FDA for use with TISSEEL. Specific instructions for the use of TISSEEL in conjunction with each cleared delivery device are provided with the device.
TISSEEL Pre-filled Syringe (Frozen)
Apply pre-filled TISSEEL using the DUO Set accessory devices provided with the product or an equivalent delivery device cleared by FDA for use with TISSEEL.
DUO Set Instructions (see Figure 1 below):
Note: Interruption of TISSEEL application causes clogging in the cannula. Replace the cannula immediately prior to resuming application. If the opening of the joining piece (Y connector) facing the cannula is clogged, use the spare joining piece provided in the package.
Figure 1 DUO SET
TISSEEL Kit (Freeze-Dried) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with and without the DUPLOJECT Preparation and Application System.
TISSEEL Pre-filled Syringe (Frozen) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with the DUO Set.
TISSEEL Kit (Freeze-Dried) and TISSEEL Kit (Freeze-Dried) with DUPLOJECT System
TISSEEL Pre-Filled Syringe (Frozen) with DUO Set
The reconstituted solution or pre-filled syringe contains:
Sealer Protein Solution
Total protein: | 96 – 125 mg/mL | |
Fibrinogen: | 67 – 106 mg/mL | |
Fibrinolysis Inhibitor (Synthetic): | 2250 – 3750 KIU/mL | |
Other ingredients include: human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection (WFI). |
Thrombin Solution
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Thrombin (Human): | 400 – 625 units/mL* | |
Calcium Chloride: | 36 – 44 µmol/mL | |
Other ingredients include: human albumin, sodium chloride and water for injection (WFI). |
Do not inject TISSEEL directly into the circulatory system or into highly vascularized tissue. Intravascular application of TISSEEL can lead to intravascular coagulation, may result in life-threatening thromboembolic events, and may increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients (see WARNINGS AND PRECAUTIONS, Use in Cardiopulmonary Surgery (5.3) and ADVERSE REACTIONS, Post Marketing (6.3)).
Do not use TISSEEL in individuals with a known hypersensitivity to aprotinin (seeWARNINGS AND PRECAUTIONS, Hypersensitivity/Allergic/Anaphylactic Reactions (5.1) and ADVERSE REACTIONS, Overall Adverse Reactions (6.1)).
Hypersensitivity or allergic/anaphylactoid reactions may occur with the use of TISSEEL. Cases (<1/10,000) have been reported in post marketing experience with Baxter's fibrin sealant (see ADVERSE REACTIONS, Post Marketing (6.3)). In specific cases, these reactions have progressed to severe anaphylaxis. Such reactions may especially be seen if TISSEEL is applied repeatedly over time or in the same setting, or if systemic aprotinin has been administered previously. Even if the first treatment was well tolerated, this may not exclude the occurrence of an allergic reaction after a subsequent administration of TISSEEL or systemic aprotinin. Observed symptoms of allergic anaphylactic reactions to TISSEEL have included: bradycardia, tachycardia, hypotension, flushing, bronchospasm, wheezing, dyspnea, nausea, urticaria, angioedema, pruritus, erythema and paresthesia. Such reactions may also occur in patients receiving TISSEEL for the first time.
Aprotinin is included in TISSEEL for its antifibrinolytic properties. Aprotinin, a monomeric polypeptide, is known to be associated with anaphylactic reactions. Even in the case of strict local application of aprotinin, there is a risk of anaphylactic reactions to aprotinin, particularly in the case of previous exposure (see CONTRAINDICATIONS, Aprotinin Hypersensitivity(4.2)). TISSEEL does not contain any substances of bovine origin.
Discontinue administration of TISSEEL in the event of hypersensitivity reactions. Mild reactions can be managed with antihistamines. Severe hypotensive reactions require immediate intervention using current principles of shock therapy. Remove remaining product from the application site.
Air or gas embolism has occurred with the use of spray devices employing pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressures and in close proximity to the tissue surface.
When applying TISSEEL using a spray device, be sure to use the pressure within the pressure range recommended by the spray device manufacturer. In the absence of a specific recommendation avoid using pressure above 20-25 psi. Do not spray closer than the distance recommended by the spray device manufacturer. In the absence of a specific recommendation avoid spraying closer than 10-15 cm from the surface of the tissue. When spraying TISSEEL, changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism. When using the EASYSPRAY device, or an equivalent spray device for open surgical procedures cleared by FDA, TISSEEL must not be sprayed in enclosed body areas and must be sprayed onto only visible application sites.
The sealer protein and thrombin solutions can be denatured by alcohol, iodine or heavy metal ions. If any of these substances have been used to clean the wound area, the area must be thoroughly rinsed before the application of TISSEEL.
Apply TISSEEL as a thin layer. Excess clot thickness may delay the natural wound healing process.
The safety and effectiveness of the combined use of TISSEEL with other biocompatible materials has not been evaluated in controlled clinical trials.
Caution should be exercised to minimize the risk of inadvertent intravascular application when using TISSEEL in cardiopulmonary bypass surgeries (see CONTRAINDICATIONS, Intravascular Application (4.1) and ADVERSE REACTIONS, Post Marketing (6.3)).
The safety and effectiveness of TISSEEL used alone or in combination with biocompatible carriers in neurosurgical procedures or other surgeries involving confined spaces have not been evaluated, and its use in this setting is not approved by FDA (see ADVERSE REACTIONS, Post Marketing (6.3) andDRUG INTERACTIONS (7)).
TISSEEL is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections, and by inactivating and removing certain viruses during the manufacturing process (see CLINICAL PHARMACOLOGY, Other Clinical Pharmacology Information (12.4)). Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for inactivation/removal of lipid enveloped viruses such as HIV, HBV, and HCV, and for the non-lipid enveloped virus such as HAV. These measures may be of limited value against small non-lipid enveloped viruses such as Parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased red blood cell turnover (e.g., hemolytic anemia) (see PATIENT COUNSELING INFORMATION (17)). ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation, telephone number 1-866-888-2472.
Hypersensitivity/Allergic/Anaphylactic Reactions: Hypersensitivity or allergic/anaphylactoid reactions may occur. In isolated cases, these reactions have progressed to severe anaphylaxis (see WARNINGS AND PRECAUTIONS, Hypersensitivity/Allergic/Anaphylactic Reactions (5.1)). No adverse events of this type were reported during clinical trials.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Increased D-Dimer levels have been observed during a clinical study in cardiovascular surgery (see CLINICAL STUDIES (14)), but did not exceed values reported in the literature occurring after this type of surgery. Postoperatively increased D-Dimers may result at least partly from the degradation of Fibrin Sealant.
Because adverse reactions are reported voluntarily and the population is of uncertain size, it is not always possible to reliably estimate the frequency of these reactions.
Manifestations of hypersensitivity or allergic reactions associated with the class of fibrin sealant/hemostatic products include: application site irritation, chest discomfort, chills, headache, lethargy, restlessness, vomiting, paresthesia and wheezing. There have been no reports of these reactions related to the specific use of TISSEEL.
The following adverse reactions have been reported in the post-marketing experience:
IMMUNE SYSTEM DISORDERS: Hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock. Anaphylactic reactions and anaphylactic shock have included fatal outcomes.
VASCULAR DISORDERS: hypotension, thromboembolism, including cerebral artery embolism and venous thrombotic cerebral infarction as a result of intravascular application
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: angioedema, erythema, impaired wound healing, pruritus, urticaria
CARDIAC DISORDERS: bradycardia, tachycardia
RESPIRATORY DISORDERS: bronchospasm, dyspnea
GASTROINTESTINAL DISORDERS: nausea
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: flushing
Air embolism associated with misapplication of fibrin sealant using the spray device, Class Effect: A post marketing fatality was reported in association with the use of another fibrin sealant when applied using a spray device. The case involved an attempt to stop active bleeding by applying the fibrin sealant using a spray device attached to a wall unit at a higher than recommended pressure for the spray device. In addition, the spray head was placed at a distance from the bleeding site that was closer than the recommended distance guidelines for the application of the sealant. The patient suffered a fatal air embolism.
There have been reports of serious adverse events such as paralysis and other compressive complications possibly related to the use of fibrin sealants in combination with resorbable hemostatic agents. There have also been reports of fatalities following the misadministration of topical thrombin (see WARNINGS AND PRECAUTIONS, Use in Neurosurgical Procedures (5.4))
Oxycellulose containing preparations may reduce the efficacy of TISSEEL and should not be used as carrier materials.
No formal interaction studies have been performed.
Pregnancy Category C
Animal reproduction studies have not been conducted with TISSEEL. It is also not known whether TISSEEL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection). TISSEEL should be given to a pregnant woman only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TISSEEL is administered to nursing mothers.
Safety and effectiveness of TISSEEL in pediatric patients have not been established.
In a Phase 3 clinical study of TISSEEL 71 out of 144 subjects were 65 and over (seeCLINICAL STUDIES (14)). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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.
TISSEEL [Fibrin Sealant], Vapor Heated, Solvent Detergent Treated, (TISSEEL) is a two-component fibrin sealant made from pooled human plasma. When combined, the two components, Sealer Protein (Human) and Thrombin (Human), mimic the final stage of the blood coagulation cascade.
Sealer Protein (Human)
Sealer Protein (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Sealer Protein (Human) is provided either as a freeze-dried powder [Sealer Protein Concentrate (Human)] for reconstitution with Fibrinolysis Inhibitor Solution (Synthetic) or as a finished frozen solution pre-filled into one side of a dual-chambered syringe (1). The active ingredient in Sealer Protein (Human) is fibrinogen. A Fibrinolysis Inhibitor, Aprotinin (Synthetic) is included in the Sealer Protein (Human) component to delay fibrinolysis. Aprotinin (Synthetic) is manufactured by solid phase synthesis from materials completely of non-human/non-animal origin.
To obtain Sealer Protein (Human), cryoprecipitate derived from the plasma is dissolved in buffer solution, solvent/detergent treated, vapor heat treated, sterile filtered and either freeze-dried in vials or frozen in pre-filled syringes.
Thrombin (Human)
Thrombin (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Thrombin (Human) is also provided either as a freeze-dried powder for reconstitution with Calcium Chloride Solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe (2).
Thrombin is prepared from plasma through a series of separation and filtration steps followed by incubation of the solution with calcium chloride to activate prothrombin to thrombin. The solution subsequently undergoes ultra/diafiltration, vapor heat treatment, solvent/detergent treatment, sterile filtration and is either freeze-dried in vials or frozen in pre-filled syringes.
Sealer Protein (Human) and Thrombin (Human) are made from pooled human plasma collected at US licensed collection centers. The vapor heat and solvent/detergent treatment steps used in the manufacturing process have been shown to be capable of significant viral reduction. No procedure, however, has been shown to be completely effective in removing viral infectivity from derivatives of human plasma (see CLINICAL PHARMACOLOGY, Other Clinical Pharmacology Information (12.4) and WARNINGS AND PRECAUTIONS, Infection Risk from Human Plasma (5.5)).
Upon mixing Sealer Protein (Human) and Thrombin (Human), soluble fibrinogen is transformed into fibrin, forming a rubber-like mass that adheres to the wound surface and achieves hemostasis and sealing or gluing of tissues.
Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein (Human) into fibrin (see Pharmacokinetics (12.3)).
Fibrinolysis Inhibitor, Aprotinin (Synthetic), is a polyvalent protease inhibitor that prevents premature degradation of fibrin. Free Aprotinin and its metabolites have a half-life of 30 to 60 minutes and are eliminated by the kidney. Preclinical studies with different fibrin sealant preparations simulating the fibrinolytic activity generated by extracorporeal circulation in patients during cardiovascular surgery have shown that incorporation of aprotinin in the product formulation increases resistance of the fibrin sealant clot to degradation in a fibrinolytic environment.
Pharmacokinetic studies were not conducted. Because TISSEEL is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.
Viral Clearance
The manufacturing procedure for TISSEEL includes processing steps designed to further reduce the risk of viral transmission. In particular, vapor heating and solvent/detergent treatment processes are included in the manufacturing of Sealer Protein Concentrate and Thrombin. Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps.
The virus reduction factors (expressed as log10) of manufacturing steps for each of the viruses tested are shown in Table 2.
n.d. = not determined HIV-1: Human Immunodeficiency Virus 1; HAV: Hepatitis A Virus; BVDV: Bovine Viral Diarrhea Virus, a model for Hepatitis C Virus;PRV: Pseudorabies Virus, a model for lipid enveloped DNA viruses, among those is Hepatitis B Virus; MMV: Mice Minute Virus, a model for B19V. |
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Manufacturing Step | Mean Reduction Factors [log10] of Virus Tested | |||||
HIV-1 | HAV | BVDV | PRV | MMV | ||
Early Manufacturing Steps | n.d. | n.d. | n.d. | n.d. | 2.7 | |
Solvent/Detergent Treatment | >5.3 | n.d. | >5.7 | >5.9 | n.d. | |
Vapor Heat Treatment | >5.5 | >5.6 | >5.7 | >6.7 | 1.2 | |
Overall Reduction Factor (ORF) | >10.8 | >5.6 | >11.4 | >12.6 | 3.9 | |
Reduction Factors for Virus Removal and/or Inactivation Thrombin Component |
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Mean Reduction Factors [log10] of Virus Tested | ||||||
Manufacturing Step | HIV-1 | HAV | BVDV | PRV | MMV | |
Thrombin Precursor Mass Capture | 3.2 | 1.5 | 1.8 | 2.5 | 1.2 | |
Vapor Heat Treatment | >5.5 | >4.9 | >5.3 | >6.7 | 1.0 | |
Solvent/Detergent Treatment | >5.3 | n.d. | >5.5 | >6.4 | n.d. | |
Ion Exchange Chromatography | n.d. | n.d. | n.d. | n.d. | 3.6 | |
Overall Reduction Factor (ORF) | >14.0 | >6.4 | >12.6 | >15.6 | 5.8 |
In addition, Human Parvovirus B19V was used to investigate the upstream Thrombin precursor mass capture step, the Sealer Protein early manufacturing steps and the Thrombin and Sealer Protein vapor heating steps. Using quantitative PCR assays, the estimated log reduction factors obtained were 1.7 and 3.4 for the Thrombin precursor mass capture step and Sealer Protein early manufacturing steps and >4 / 1.0 for the Thrombin / Sealer Protein vapor heating steps, respectively.
TISSEEL was evaluated in a prospective, parallel design, randomized (1:1), double-blind, multicenter clinical study against an earlier formulation of the product, TISSEEL VH, in 317 subjects undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) and median sternotomy. Patients were treated with TISSEEL or the control product only when hemostasis was not achieved by conventional surgical methods. For the endpoint, hemostasis achieved at the primary treatment site within 5 minutes of treatment and maintained until closure of the surgical wound, TISSEEL was non-inferior to the earlier formulation of the product using a one-sided 97.5% confidence interval on the difference in the proportion of subjects successfully treated.
TISSEEL | TISSEEL VH | |
Intent to Treat Analysis | 127/144 (88.2%) | 129/144 (89.6%) |
Per Protocol Analysis | 108/123 (87.8%) | 122/135 (90.4%) |
An earlier formulation of TISSEEL was evaluated in an open-label crossover study against control topical hemostatic agents in 489 patients undergoing cardiovascular reoperation or resternotomy at 11 institutions. Patients were randomized to TISSEEL or control hemostatic agents when a topical hemostatic was needed at the conclusion of surgery and after all attempts at surgical hemostasis. Patients were crossed to the alternative therapy if bleeding continued after the 5 minute endpoint. At 10 centers, TISSEEL was used after administration of protamine sulfate. At one site, TISSEEL could be used before administration of protamine sulfate. 365 of the 489 patients developed bleeding episodes requiring treatment. For the endpoint (successful hemostasis at 5 minutes), TISSEEL was statistically significantly superior to control topical hemostatic agents in these patients. Similarly, absolute time to cessation of bleeding was statistically significantly shorter for TISSEEL than for control topical hemostatic agents (p<0.0001, Gehan-Wilcoxon test, two sided).
TISSEEL | Control Topical Hemostatic Agent |
82.4% (159/193) | 44.5% (76/172) |
Pearson χ2 two sided; p <0.0001; intent-to-treat analysis |
In a single center, open label trial, an earlier formulation of TISSEEL was compared to historical controls in patients undergoing laparotomy for blunt or penetrating traumatic injury to the spleen and/or liver. Use of TISSEEL resulted in the need for statistically significantly fewer splenectomies than control hemostatic maneuvers (Refer to Table 5). TISSEEL did not result in significantly reduced mortality in patients with blunt or penetrating trauma to the liver alone or to the liver and spleen (p=0.067, χ2, one sided).
Injury to: | TISSEEL | Historic Controls | |
Spleen | 0/19 | 14/22 | p <0.001 |
Spleen and liver | 1/26 | 19/34 | p <0.001 |
In a single center, prospective open label study of 120 patients randomized to standard of care (59 patients) or standard of care plus fibrin sealant (61 patients) for elective colostomy closure after temporary colostomy placement for treatment of traumatic injury to the colon, the earlier version of TISSEEL plus standard of care was also shown to be significantly superior to standard of care alone (p=0.0406, Jonckheere-Terpstra test for ordinal data, two sided) with regard to anastomotic complications (leakage, intra-abdominal abscess formation, re-operation, septic shock, and death).
TISSEEL is supplied in the following pack sizes and presentations:
Pack Size | TISSEEL Kit (Freeze-Dried) | TISSEEL Kit (Freeze-Dried) with DUPLOJECT System | |
TISSEEL Pre-Filled Syringe (Frozen) with DUO Set | |||
2 mL | 0944-4201-03 | 0944-4201-04 | 0944-8402-02 |
4 mL | 0944-4201-07 | 0944-4201-08 | 0944-8402-04 |
10 mL | 0944-4201-11 | 0944-4201-12 | 0944-8402-10 |
Storage
TISSEEL Kit (Freeze-Dried)
Store at 2°C to 25°C. Avoid freezing. After reconstitution, the product must be used within 4 hours. Do not freeze or refrigerate reconstituted solutions.
TISSEEL Pre-filled Syringe (Frozen)
Long term: | Store at ≤ -20°C. |
Short term: |
Room Temperature Thawing: Unopened pouches may be stored for up to 48 hours at room temperature (15-25°C). Quick Thawing: Maintain the product at 33-37°C until use. If the package is opened or warmed to 33-37°C it must be used within 4 hours. Do not refrigerate or re-freeze after thawing. Do not microwave. |
Do not use after the expiration date. Discard if packaging of any components is damaged.
Because this product is made from human plasma, the physician should discuss the risks and benefits of this product with the patient.
Instruct patients to consult their physician if symptoms of B19 virus infection appear (fever, drowsiness, chills and runny nose) followed about two weeks later by a rash and joint pain (see USE IN SPECIFIC POPULATIONS, Pregnancy (8.1)).
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
US License No. 140
This product is covered by US Patent No. 5,962,405.
Baxter, Duo, Duploject, Easyspray, Fibrinotherm and Tisseel are trademarks of Baxter International Inc.
TISSEEL Pre-filled syringe 10 mL unit carton
Fibrin Sealant
TISSEEL
10 mL
NDC 0944-8402-10
Vapor Heated, Solvent/Detergent Treated, Frozen
Pre-filled Syringe
TOPICAL USE ONLY
DO NOT INJECT
Contents:
Pre-filled syringe containing:
Sealer Protein Solution (1): 5 mL, sterile
Sealer Protein (Human)
Fibrinolysis Inhibitor (Aprotinin, Synthetic), 3000 KIU/mL
Thrombin Solution (2): 5 mL, sterile
Thrombin (Human), 500 units/mL
Calcium Chloride, 40 μmol/mL
The risks and benefits of this product should be discussed with the patient.
Rx Only
Store at -20ºC (-4ºF) or colder.
Read directions for thawing and application before use.
Thawed, unopened pouches may be stored for up to 48 hours at room temperature (15-25ºC) after removal from the freezer.
Do not refrigerate or re-freeze.
Latex free
For single use only.
TISSEEL 10 mL Pre-filled syringe pouch label
Fibrin Sealant
TISSEEL
10 mL
NDC 0944-8402-10
Vapor Heated, Solvent/Detergent Treated, Frozen
Contents:
Pre-filled syringe containing:
Sealer Protein Solution (1): 5 mL, sterile
Sealer Protein (Human)
Fibrinolysis Inhibitor (Aprotinin, Synthetic), 3000 KIU/mL
Thrombin Solution (2): 5 mL, sterile
Thrombin (Human), 500 units/mL
Calcium Chloride, 40 μmol/mL
Read directions for thawing and application before use.
NOT FOR INJECTION.
Store at -20ºC (-4ºF) or colder. Thawed, unopened pouches may be stored for up to 48 hours at room temperature (15-25ºC) after removal from the freezer. Do not refrigerate or re-freeze.
Rx Only
BAXTER and TISSEEL are trademarks of Baxter Healthcare International Inc., registered in the U.S. Patent and Trademark Office.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
TISSEEL 10 mL Pre-filled syringe barrel label
Fibrin Sealant
TISSEEL 10 mL
TISSEEL 10 mL kit unit carton
Fibrin Sealant
TISSEEL
10 mL
NDC 0944-4201-11
Vapor Heated, Solvent/Detergent Treated, Kit
Contents:
Sealer Protein Concentrate (Human), Vapor Heated, Solvent/Detergent Treated, freeze dried, sterile, for 5 mL of Sealer Protein Solution
Fibrinolysis Inhibitor Solution (Synthetic), sterile, 3000 KIU of Aprotinin/mL
Thrombin (Human), Vapor Heated, Solvent/Detergent Treated, freeze dried, sterile, for 5 mL of Thrombin Solution 500 units/mL
Calcium Chloride Solution, sterile, 40 μmol/mL
The risks and benefits of this product should be discussed with the patient.
Read directions for reconstitution and application before use.
Use within four hours of reconstitution.
NOT FOR INJECTION.For single use only.
Latex free
Rx Only
Thrombin (Human) 5 mL vial label
Thrombin (Human)
NDC 0944-7332-05
Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile
Reconstitute with 5 mL of Calcium Chloride Solution
Concentration: 500 units/mL
Use within 4 hours of reconstitution.
Read enclosed directions prior to use.
NOT FOR INJECTION. Store at 2ºC to 25ºC.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
Rx only
Calcium Chloride Solution 5 mL vial label
Calcium Chloride Solution
NDC 0944-7401-05
Sterile
For reconstitution of freeze-dried Thrombin (Human),
Contents: 5 mL
Concentration: 40 μmol/mL
NOT FOR INJECTION. Store at 2ºC to 25ºC.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
Rx only
Fibrinolysis Inhibitor Solution (Synthetic) 5 mL vial label
Fibrinolysis Inhibitor Solution (Synthetic)
NDC 0944-7201-05
Sterile
For reconstitution of freeze-dried Sealer Protein Concentrate (Human),
Contents: 5 mL
Concentration: 3000 KIU of Aprotinin/mL
NOT FOR INJECTION. Store at 2ºC to 25ºC.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
Rx only
Sealer Protein Concentrate (Human) 5 mL vial label
Sealer Protein Concentrate (Human)
NDC 0944-7112-05
Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile
Reconstitute with 5 mL of Fibrinolysis Inhibitor Solution (Synthetic)
Vial contains a stirrer to facilitate reconstitution.
Use within 4 hours of reconstitution.
Read enclosed directions prior to use.
NOT FOR INJECTION. Store at 2ºC to 25ºC.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
Rx only
TISSEEL
FROZEN
fibrinogen human and thrombin human solution |
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TISSEEL
fibrinogen human and thrombin human kit |
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Labeler - Baxalta US Inc. (079887619) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Baxter Aktiengesellschaft | 300434670 | MANUFACTURE |