(Human), Vapor Heated, Solvent/Detergent Treated 500 IU
Contents
1. LAAS J Zus tzliche Abdichtung von Pleura L sionen mit Fibrinkleber Klinische Studie 1981 STAINDL O Beitrag zur chirurgischen Behandlung gutartiger Trachealstenosen Wr Med Wschr 128 175 177 1978 VECSEY D ber eine neue Methode der Blutstillung mit Klebematerial bei der Adenomektomie Urologie und Nephrol 73 57 62 1980 HENNING K PFL GER H RAUCHENWALD K URLESBERGER H Klinische Erfahrung mit Fibrinkonzentrat in der Nierenparenchymchirurgie Helv chir Acta 47 297 1980 RAUCHENWALD K HENNING K URLESBERGER H Humanfibrinklebung bei Nephrotomie Helv chir Acta 45 283 286 1978 REDL H SCHLAG G DINGES H P Methods of Fibrin Seal Application Thorac Cardiovasc Surg 30 223 227 1982 HENNRICH N BR MMER W 3 Bericht Trypsin Inhibitor Pharm Ind 35 272 273 1973 ROBERTSON I GAFFNEY P J BANGHAM D R Standard for human thrombin Thrombos Diathes Haemorrh Stuttgart 34 3 18 1975 Page 40 of41 20 2il 22 23 24 25 26 REDL H et al Grundlagen der Fibrinklebung In Fibrinkleber in Orthop die und Traumatologie 4 Heidelberger Orthop die Symposium H Cotta A Braun Eds Georg Thieme Verlag 18 21 1982 Validation of Virus Removal and Inactivation in the Course of the Manufacture of Sealant Protein Concentrate Human Vapor Heated without Creatine Using HIV 1 HAV and Model Viruses Validation of Virus Removal and Inactivation by DEAE Adsorption2. HCV HIV or B19V Baxter clinical study 550003 Although viral safety was not an endpoint in the other clinical studies any issues concerning viral safety would have been detected and followed up in the process of AE reporting No reports concerning viral transmission from any studies involving Fibrin Sealant 4 IU ARTISS or 500 IU TISSEEL were received Page 35 of 41 The therapeutic activities of TISSEEL are hemostasis gluing and sealing of tissue and the support of wound healing Physiologically the process of wound closure starts when a bleeding ceases In places where injured blood vessels lie open hemostatic plugs form of platelets and fibrin which become more and more solid as other blood cells particularly erythrocytes are involved Because the bleeding ceases blood that has escaped into the wound bed earlier coagulates In a next step fibrin in both the coagulated blood and hemostatic plug retracts plasma is squeezed out the blood vessels contract and the wound area becomes smaller As various cells begin to proliferate into the retracted blood coagula wound healing sets in In developing Fibrin Sealant this principle has at least partly been simulated by applying a highly concentrated fibrinogen solution which also contains factor XIII as co fractionated from the plasma and a solution of thrombin and calcium chloride to the wound area where the mix coagulates Since the Sealant does not contain thrombocytes the
3. TISSEEL should only be reconstituted and administered according to the instructions and with the devices recommended for this product see WARNINGS AND PRECAUTIONS General Regarding spray applications see WARNINGS AND PRECAUTIONS Application Precautions for specific recommendations on the required pressure and distance from tissue per surgical procedure and length of applicator tips The setting rate depends on the concentration of the human Thrombin as contained in the Thrombin Calcium Chloride solution used The TISSEEL Thrombin component is provided in a 500 IU mL concentration TISSEEL 500 IU Fast Set A 4 IU mL Thrombin concentration is also available and marketed as ARTISS 4 IU Slow Set Prior to application TISSEEL must be warmed to 33 C to 37 C TISSEEL must not be exposed to temperatures above 37 C and must not be microwaved The sealer protein and the thrombin solutions should be clear or slightly opalescent Do not use solutions that are cloudy or have deposits Inspect products for particulate matter and discoloration prior to application Before application of TISSEEL ensure that parts of the body outside the desired application area are sufficiently covered to prevent tissue adhesion at undesired sites Prior to applying TISSEEL the surface area of the wound needs to be dried by standard techniques e g intermittent application of compresses swabs use of suction devices Apply TISSEEL as a thin layer The initial
4. For application the double chamber syringe with the Sealer Protein Solution and the Thrombin Solution has to be connected to a joining piece and an application cannula Tether Strap E Double Plunger N Double Chamber Syringe Joining piece ZA Application Canula Operating Instructions Remove the cap covering the nozzles of the double chamber syringe Connect the nozzles of the double chamber syringe to the joining piece ensuring that they are firmly fixed Secure the joining piece by fastening the tether strap to the double chamber syringe Should the pull strap tear use the spare joining piece If none is available further use is still possible but tightness of the connection needs to be ensured to prevent any risk of leaking Fit an application cannula onto the joining piece Fit the double plunger to the end of the syringe chamber Page 22 of 41 Do not expel the air remaining inside the joining piece or application cannula until you start actual application as the aperture of the cannula may clog otherwise Apply the mixed Sealer Protein Thrombin Solution onto the recipient surface or surfaces of the parts to be sealed If application of the fibrin sealant components is interrupted clogging may occur in the cannula To resume application replace the application cannula with a new one If the apertures of the joining piece are clogged use the spare joining piece provided in the Duo Set b Simultaneous Application
5. Lyophilization and Vapor Heating in the Course of the Manufacture of Thrombin Human Vapor Heated Using HIV 1 and Model Viruses Validation of Virus Inactivation by Vapor Heating of Thrombin Human Using Hepatitis A Virus A Study to Determine the Safety of Virus Inactivated Factor Concentrates in Hemophiliacs Naive to Blood Product Administration International Factor Safety Study Part II Antihemophilic Factor Factor VIII Concentrate Human IMMUNO Vapor Heated Evaluation as of February 23 1994 A Study to Determine the Safety of Virus Inactivated Factor Concentrates in Hemophiliacs Naive to Blood Product Administration International Factor Safety Study Part II Factors VII and IX Evaluation as of March 1 1995 Spontaneous Adverse Experience Reports TISSUCOL TISSEEL KIT Two Component Fibrin Sealant Freeze Dried Steam Treated January 01 1990 to December 31 1995 Page 41 of 41
6. Using Spray Set and EASYSPRAY Caution must be used when applying fibrin sealant using pressurized air or gas e Any application of pressurized air or gas is associated with a potential risk of air embolism tissue rupture or gas entrapment with compression which may be life threatening e TISSEEL must be sprayed only onto application sites that are visible Spray Set and EASYSPRAY can be connected to TISSEEL Kit see drawing below and TISSEEL Frozen in the same way Note For operation instructions please refer to the Instructions for Use provided together with Spray Set and Easy Spray EasySpray device gt Spray head Pressure line Page 23 of 41 The Spray Set is particularly suitable for spraying of larger areas e g to control oozing of parenchymatous organs or to adhere skin grafts The two components are sprayed simultaneously using sterile propellant gas via EASYSPRAY and the volume of the Solutions ejected is controlled with the DUPLOJECT System DUO Set plunger The user must follow the instructions and precautions in the Spray Set and EASYSPRAY device user manual for example regarding the need to limit the gas pressure to a maximum of 2 bars Spray at a minimum distance of 10 cm Only use application devices licensed for the administration of TISSEEL c Simultaneous Application Using DUPLOCATH Application Catheters or other accessories provided by Baxter In operation sites where access is difficult
7. axillary vein thrombosis and hypotension No adverse events related to TISSEEL 500 IU Fast Set were reported from a study in hip joint replacement from the 53 patients treated with the product The related adverse events of the cardiovascular surgery study and the lymph node dissection study are listed according to their system organ class in the table below Frequencies are based on patients treated in the respective studies because the indications of the two studies were too different to pool the data Page 11 of 41 System Organ Class Adverse events Preferred Term TISSEEL 500 IU Number of events Number of patients treated Blood and lymphatic system Fibrin D Dimer increased 2 of 157 disorders Increase of Fibrin degradation 1 of 79 products Nervous system disorders Sensory disturbance 1 of 79 Gastrointestinal disorders Nausea 2 of 79 Skin and subcutaneous tissue Rash 1 of 79 disorders Musculoskeletal and connective Pain in extremity 4 of 79 tissue disorders Infections and infestations Postoperative wound infection 2 of 79 Injury poisoning and procedural E 13 of 79 complications Vascular disorders Axillary vein thrombosis 1 of 79 Hypotension 1 of 79 oe diso Hes and M Procedural Pain 2 of 79 administration site conditions Pain 1 of 79 Body temperature increased 1 of 79 Post Market Adverse Drug Reactions The adverse reactions listed below reflect what has been reported
8. 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 centres TISSEEL HT was used after administration of protamine sulfate At one site TISSEEL HT could be used before administration of protamine sulfate 365 of the 489 patients developed bleeding episodes requiring treatment In these patients for the endpoint successful hemostasis at 5 minutes TISSEEL HT was statistically significantly superior to control topical hemostatic agents Hemostasis within 5 minutes Predecessor TISSEEL HT Control Topical Hemostatic Agent 82 4 159 193 44 5 76 172 Pearson x two sided p lt 0 0001 intent to treat analysis Similarly absolute time to cessation of bleeding was statistically significantly shorter for TISSEEL HT than for control topical hemostatic agents p lt 0 0001 Wilcoxon Gehan test two sided In a single center open label trial an earlier formulation of TISSEEL HT was compared to historical controls in patients undergoing laparotomy for blunt or penetrating traumatic injury to the spleen and or liver Use of TISSEEL HT resulted in the need for statistically significantly fewer splenectomies than control hemostatic maneuvers Splenectomy Rate Injury to Predecessor Historic Controls TISSEEL HT Spleen 0 19 14 22 p lt 0 001 Spleen and liver 1 26 19 34
9. p lt 0 001 TISSEEL HT 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 a one sided 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 Page 33 of 41 version of TISSEEL HT 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 DETAILED PHARMACOLOGY The substances in the TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated Kit are used to prepare two components Sealer Protein Solution and Thrombin Solution Sealer Protein Solution is produced by dissolving Sealer Protein Concentrate in Aprotinin Solution Freeze dried Thrombin dissolved in Calcium Chloride Solution yields the Thrombin Solution The assembly for TISSEEL Frozen is reflecting the composition of the Kit components after reconstitution filled in a double chamber syringe which is stored in a deep frozen condition Sealer Protein Concentrate Aprotinin syringe chamber 1 and Thrombin Ca
10. that has been used for dilution of Aprotinin Solution Allow vial to stand at 37 C for one minute Swirl briefly and vigorously with a circular motion avoid excessive frothing and replace vial into water bath for another 10 15 minutes Reconstitution of freeze dried Sealer Protein Concentrate is complete as soon as no undissolved particles are detectable in transparent light Otherwise swirl again briefly and keep vial at 37 C for a few more minutes Draw up Sealer Protein Solution into a sterile blue scaled syringe using aseptic precautions insert a needle through the rubber stopper at its center to allow access of air Note If not used immediately keep Sealer Protein Solution at 37 C or at room temperature without stirring if it is not to be used immediately Before use the solution should be warmed to 37 C The maximum holding time of 4 hours upon reconstitution must not be exceeded To ensure homogeneity swirl with a circular motion avoid frothing before drawing up the solution b How to Prepare Thrombin Solution Remove the flip off caps from the vial containing Thrombin and the vial containing Calcium Chloride Solution disinfect the rubber stoppers of both vials with a germicidal solution and allow to dry Do not use iodine containing preparations such as betadine for disinfection Transfer the contents of the vial with Calcium Chloride Solution into the vial containing the freeze dried Thrombin using the sterile r
11. 2 0 mL 5 0 mL of Human Concentrate to be reconstituted sterile frozen TISSEEL Sealer with one vial 1 0 mL 2 0 mL 5 0 ml of Protein Human Aprotinin Aprotinin Solution sterile Solution so 2m I IU mL 10 mL One vial lyophilized Thrombin Human 1 0 mL 2 0 mL 5 0 mL of 500 IU to be reconstituted with one vial sterile frozen Thrombin Human 1 0 mL 2 0 mL 5 0 mL of Calcium Calcium Chloride Solution Chloride Solution sterile Page 27 of 41 TISSEEL Kit also contains DUPLOJECT System the Kit for Reconstitution and Application consisting of 4 transfer needles 2 blue scaled syringes 2 black scaled syringes 1 DUPLOJECT two syringe clip 2 joining pieces and 4 application cannulas TISSEEL Frozen also contains DUO Set the sterile accessory devices consisting of 1 plunger 2 joining pieces and 4 application cannulas See the following Accessories Section for more accessories for use with TISSEEL Composition TISSEEL 500 IU Kit consists of 4 separate vials containing Sealer Protein Human Aprotinin Solution Thrombin Human and Calcium Chloride Solution TISSEEL 500 IU Frozen consists of a double chamber syringe containing Sealer Protein Aprotinin Solution syringe body 1 and Thrombin Calcium Chloride Solution syringe body 2 After reconstituting the vials in the Kit the resulting concentrations of the Sealer Protein Aprotinin solution and the Thrombin Calcium Chloride solution are the same as those in t
12. C to 37 C TISSEEL in pre filled syringe frozen may be thawed under controlled conditions using one of the three following options Option 1 Thawing on the sterile field using a Sterile Water Bath 33 C to 37 C sterile water bath transfer double chamber syringe set and the inner pouch to the sterile field remove the double chamber syringe with pre filled syringes from inner pouch and place directly into sterile water bath Ensure the double chamber syringe is completely immersed under the water Approximate thawing and warming times when using this method are Thawing Warming Times 33 C to 37 C Sterile Water Bath Pack Size 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 double chamber syringe in two pouches maintain the double chamber syringe set 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 Page 18 of 41 water bath after thawing dry external pouch and transfer inner pouch and pre filled syringes onto the sterile field Approximate thawing and warming times when using this method are Thawing Warming Times 33 C to 37 C Non Sterile Water Bath Pack Size In Pouches 2 mL 30 minutes 4 mL 40 minutes 10 mL 80 minutes Option 3 Thawing of
13. ISSEEL 500 IU Fast Set Fibrin Sealant Human Vapor Heated Solvent Detergent Treated is available in two different dosage forms Kit and Frozen TISSEEL Kit consists of 2 vials containing powder preparations of Sealer Protein Concentrate and Thrombin and two vials containing liquid preparations of Aprotinin and Calcium Chloride The Sealer Protein Concentrate is reconstituted with the Aprotinin and produces a solution that is referred to as the Sealer Protein Aprotinin Solution Thrombin is reconstituted with the Calcium Chloride Solution which produces a solution that is referred to as the Thrombin Calcium Chloride Solution These two solutions are applied using an application device described in the DOSAGE AND ADMINISTRATION Method of Application section TISSEEL Kit is available in 2 4 and 10 mL pack sizes 1 2 and 5 mL reconstituted Sealer Protein Solution and 1 2 and 5 mL reconstituted Thrombin Solution TISSEEL Frozen consists of a pre filled double chamber syringe containing Sealer Protein Aprotinin Solution and Thrombin Calcium Chloride Solution TISSEEL Frozen is available in 2 4 and 10 mL pack sizes Dosing Considerations For topical use only do not inject Dry the site of application Prior to applying TISSEEL the surface area of the wound needs to be dried by standard techniques e g intermittent application of compresses swabs use of suction devices Do not use pressurized air or gas for drying the site Recommen
14. ND PRECAUTIONS Page 25 of 41 ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated is a tissue glue with sealing hemostyptic and gluing properties which does not interfere with but may enhance wound healing The action of TISSEEL simulates key features of the physiological process of wound closure A highly concentrated fibrinogen Aprotinin solution which among other ingredients contains Factor XIII co fractionated from the plasma and a solution of thrombin and calcium chloride are applied to the wound area where the mixture coagulates The presence of Factor XIII causes the fibrin to crosslink which gives the coagulum additional resilience Aprotinin prevents premature degradation of the clot Pharmacodynamics Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein Human into fibrin Part of the thrombin is adsorbed by the fibrin and any excess thrombin is inactivated by protease inhibitors in the blood Fibrinolysis Inhibitor Aprotinin is a polyvalent protease inhibitor that prevents premature degradation of fibrin Free Aprotinin has a half life t 1 2 of approx 0 82 and is 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 incorporati
15. PRODUCT MONOGRAPH Pr TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated 500 IU Fast Set in two presentation forms Kit Lyophilized Powders with Diluents for Topical Application Frozen Solutions for Thawing for Topical Application Hemostatic Agent Baxter Corporation Date of Revision Mississauga ON March 31 2015 Canada LSN 0C2 Submission Control No 183459 Date of Approval June 19 2015 Page of 41 Table of Contents 1 PART I HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 111111e1ititi t titrnes t nrten ent nrsernrn tarnrn entara t 3 DESCRIP VION ea ne ee ee E 3 INDICATIONS AND CLINICAL USE sen eege 4 CONTRAINDICATION hie ae ea 5 WARNINGS AND PRPCAUTIONS EE 6 EE 10 DRUG INFRACTIONS nn ana ana 13 DOSAGE AND ADMINISTRATION 14 EE 25 ACTION AND CLINICAL PHARMACOLOGY 111115111i1i itii trtenee tsietatea n 26 STORAGE AND S TABIIIY nee ee 26 DOSAGE FORMS COMPOSITION AND PACKAGING j ssssssssssssssssesssstssnssssesenstnsnssee 27 EECH 29 2 PART II SCIENTIFIC INFORMATION EE 30 PHARMACEUTICAL INFORMATION 30 EEN 32 RECHERCHES 34 TOXICOLOGY ee 37 3 PART II CONSUMER INFORMATION 39 PATIENT COUNSELLING INFORMATION 39 Page 2 of 41 TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated 500 IU mL 1 PART I HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form Strength Clinically Relev
16. al in vitro study comparing both TISSEEL preparations frozen and lyophilized and the predecessor product TISSEEL VH lyophilized Kit In summary presented in vitro and in vivo data support the equivalence of TISSEEL frozen and lyophilized with the predecessor product TISSEEL VH lyophilized Kit Moreover it was shown that synthetic Aprotinin has no negative impact on the safety of the Fibrin Sealant Long term animal studies to evaluate the carcinogenic potential of TISSEEL or studies to determine the effect of TISSEEL on fertility have not been performed On the following page the toxicology program is presented The composition of TISSEEL frozen thawed is identical to the composition of the reconstituted TISSEEL freeze dried Page 37 of 41 Toxicology program for Baxter Fibrin Sealants Study Type A e Species Test Article Single dose Toxicity S C Rat TISSEEL frozen Single dose Toxicity S C Rabbit TISSEEL frozen Single dose Toxicity S C Rat TISSEEL s apr frozen Single dose Toxicity S C Rabbit TISSEEL s apr frozen Single dose Toxicity i v Mouse Synthetic Aprotinin Single dose Toxicity i v Rat Synthetic Aprotinin Genotoxicity i v E coli TISSEEL frozen Genotoxicity i v SE Synthetic Aprotinin Local Tolerance s c spongiosa blocks Rat TISSEEL frozen Local Tolerance s c spongiosa blocks Rabbit TISSEEL frozen Local Tolerance s c spongiosa blocks Rat TISSEEL s apr froz
17. amount of the product to be applied should be sufficient to entirely cover the intended application area If TISSEEL does not fully adhere to tissue and bleeding continues remove TISSEEL clot and repeat application Ensure that the two components are quickly and thoroughly mixed which is essential for TISSEEL to gain the optimum strength The Spray Set is particularly suitable for spraying of larger areas In operation sites where access is difficult or when using an endoscope or trocar TISSEEL can be applied using DUPLOCATH Application Catheters or DuploSpray MIS Surgical Sealant Delivery System With the use of TISSEEL 500 IU mL the clotting process commences within seconds After TISSEEL has been applied allow at least 2 minutes to achieve sufficient Page 20 of 41 polymerization Once turbid TISSEEL can no longer be manipulated Solidified Sealant reaches its ultimate strength after about two hours 70 after about ten minutes a Simultaneous Application using application cannula contained in DUPLOJECT System or DUO Set i Administration using DUPLOJECT System For application clip the two single use syringes with the reconstituted Sealer Protein Solution and Thrombin Solution into the DUPLOJECT Two Syringe Clip and connect this assembly to a joining piece and an application cannula The common plunger of the DUPLOJECT Two Syringe Clip ensures that equal volumes are fed through the joining piece before being mixed in
18. ant Administration Nonmedicinal Ingredients Topical 500 IU Fast Set TISSEEL Lyophilized Powders with Diluents 2 0 mL 4 0 mL 10 0 mL total volume For a complete listing see Dosage Forms Composition and or Packaging Section Frozen Solutions for Thawing 2 0 mL 4 0 mL 10 0 mL total volume DESCRIPTION TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated 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 TISSEEL is intended only for topical administration 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 Synthetic Aprotinin Solution or as a finished frozen liquid Sealer Protein Aprotinin Solution pre filled into one side of a double chamber syringe chamber containing Sealer Protein Aprotinin Solution is marked as 1 The active ingredient in Sealer Protein Human component is fibrinogen In addition Factor XIII is co purified with clottable protein from human plasma No Factor XIII is added to the Sealer Protein Human manufacturing process resulting in a Factor XIII level of 0 6 10 U mL in the drug
19. as been evaluated in a clinical trial involving a number of geriatric patients No overall differences in safety or effectiveness were observed between these subjects and younger subjects Pediatrics 1 1 16 years of age or lt 16 years of age Efficacy and safety in use of Fibrin Sealant has been evaluated in a clinical trial involving also a group of pediatric patients and was not found to be different from an adult population CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container For a complete listing see the DOSAGE FORMS COMPOSITION AND PACKAGING Section of the product monograph TISSEEL should not be used in individuals with a known hypersensitivity to Aprotinin TISSEEL is contraindicated for intravascular application Intravascular application may result in life threatening thromboembolic events For the treatment of massive and brisk arterial or venous bleeding TISSEEL alone is not effective and not indicated for this treatment Page 5 of 41 WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Intravascular application of TISSEEL can lead to intravascular coagulation may result in life threatening thromboembolic events and might increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients Especially in coronary bypass surgery TISSEEL should be applied with caution to minimize any ri
20. clotted fibrin does not appreciably retract When the mixture is applied however the fibrin concentration in the coagulum is the same as or higher than that of a retracted hemostatic plug To preserve the coagulum until the wound healing has reached a stage where it is no longer required the Sealant has been designed to contain a fibrinolysis inhibitor The fibrin in the Sealant adheres perfectly to the wound edges guaranteeing adequate sealing effect Similar to the hemostatic plug wound healing is promoted by the fibrin applied Combined application of Sealant with a mixture of autologous or homologous spongiosa provides excellent plugging material for bone defects Using adequate technique TISSEEL is also an excellent tool in sealing autologous or homologous cartilage and bone TISSEEL and all of its components have not been observed to affect systemic circulation respiration or the central nervous system This is attributable to both the fact that only minimal quantities of each single component are applied compared to their use for other indications and the fact that TISSEEL becomes only locally effective The mechanism underlying solidification of tissue and persistence of a solidified clot have been investigated in numerous studies As a biologic material Fibrin Sealant becomes completely absorbed at a rate which depends both on the fibrinolytic activity of the surrounding tissue and the quantity of Fibrinolysis Inhibitor added In t
21. ded Dose and Dosage Adjustment Dosage of TISSEEL i e the amount applied is individualized based on the application area and purpose of use Only a thin layer of TISSEEL should be applied Excessive thickness of the fibrin layer may interfere with the product s efficacy and the wound healing process The application can be repeated if necessary However avoid re application to a pre existing polymerized TISSEEL layer as TISSEEL may not adhere firmly to a polymerized layer If used for tissue adherence it is recommended that the initial application cover the entire Page 14 of 41 intended application area The amount of TISSEEL to be applied 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 Area to be sealed cannula Area to be sealed using Required package size of catheter compressed gas spray TISSEEL application 8 cm 25 100 cm 2 mL 16 cm 50 200 cm 4 mL 40 cm 125 500 cm 10 mL Administration Various methods can be used to simultaneously apply the two components of TISSEEL a using application cannula contained in DUPLOJECT System DUO Set b using Spray Set and EASYSPRAY c using DUPLOCATH Application Catheters or other accessories provided by Baxter d using DUPLOSPRAY MIS regulator applicator and tips 1 Preparation of TISSEEL Kit Freeze Dried The following instructions are for the r
22. disperses the combined TISSEEL components for application of a thin layer to an open or shallow treatment site The spray output is adjustable from a coarse to fine droplet size and a foot switch activates the gas flow When using the DuploSpray MIS spray device for minimally invasive surgery it should not be sprayed closer than 2 cm Page 24 of 41 A diagram of the DUPLOSPRAY MIS REGULATOR is provided below Note For operation instructions please refer to the Instructions for Use provided together with DuploSpray MIS Applicator and DuploSpray MIS Regulator Gluing of Tissue After the two components have been applied approximate the wound areas Fix or hold the glued parts in the desired position for three to five minutes to ensure that the setting Sealant adheres firmly to the surrounding tissue Solidified Sealant reaches its ultimate strength after about two hours 70 after about ten minutes OVERDOSAGE No symptoms of overdose are known for TISSEEL As the product is actively used by the surgeon overdose is very unlikely to occur TISSEEL is only to be used by a physician in a hospital setting Only a thin layer of TISSEEL should be applied to avoid the formation of excess granulation tissue and to ensure gradual absorption of the polymerized fibrin sealant Excessive thickness of the fibrin layer may negatively interfere with the product s efficacy and the wound healing process See DOSAGE AND ADMINISTRATION and WARNINGS A
23. econstitution components provided with the DUPLOJECT System Swirl briefly Place the vial into the adapted opening of the FIBRINOTHERM device or Water Bath Reconstitution of Thrombin is complete when all of the Thrombin concentrate is dissolved Keep the Thrombin Solution at 37 C or at room temperature without stirring if it is not to be used immediately Before use the solution should be warmed to 37 C c 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 Page 17 of 41 2 Preparation of TISSEEL Frozen in pre filled syringes Do not use TISSEEL unless it is completely thawed and warmed liquid consistency Do not remove the protective syringe cap until thawing is complete and application tip is ready to be attached Room Temperature Thawing Approximate thawing times when using this method are Pack Size Thawing Time at Room Temperature In Pouches 2 mL 60 minutes 4 mL 110 minutes 10 mL 160 minutes Unopened pouches of TISSEEL 500 IU Fast Set thawed at room temperature may be stored for up to 7 days at room temperature 15 C 25 C after removal from the freezer Prior to use the product should be warmed to 33
24. econstitution of TISSEEL Kit using the DUPLOJECT System provided within the Kit However an equivalent device can also be used For operation instructions please refer to the Instructions for Use provided together with this device Check for appropriate component colour coding before reconstitution of the component Prior to reconstitution of TISSEEL the rubber stoppers of all vials should be cleansed After reconstitution the product must be used within 4 hours Reconstituted solutions must not be refrigerated or frozen Vials are for single use only Note Do not use the syringes and needles previously used for reconstitution of one component for the reconstitution of the other component to prevent premature setting Direct contact between disinfectant and product must be avoided See DRUG INTERACTIONS Page 15 of 41 a How to Prepare TISSEEL Sealer Protein Solution Freeze dried Sealer Protein Concentrate is reconstituted in the Aprotinin Solution of 3 000 KIU mL using the FIBRINOTHERM warming and stirring device recommended method Alternatively a sterile water bath at a temperature of 33 C to 37 C can be used i Reconstitution of Freeze Dried Sealer Protein Concentrate Using FIBRINOTHERM device For ease of handling a combined heating and stirring device FIBRINOTHERM has been developed to meet the specific requirements of reconstituting freeze dried Sealer Protein Concentrate FIBRINOTHERM is a thermoblock with a magn
25. ektomie Vorl ufige Mitteilung In Fibrinogen Fibrin und Fibrinkleber F K Schattauer Verlag 271 273 1980 ROUSOU J LEVITSKY S COSGROVE D et al Randomized Clinical Trial of Fibrin Sealant in Patients Undergoing Resternotomy of Reoperation After Cardiac Operations In The Journal of Thoracic and Cardiovascular Surgery Vol 97 No 2 194 203 1989 WOLNER E Fibrin Gluing in Cardiovascular Surgery Thorac Cardiovasc Surg 30 Georg Thieme Verlag Stuttgart N York 236 237 1982 MARCZELL A EFFERDINGER F SPOULA H STIERER M Anwendungsbereiche des Fibrinklebers in der Abdominalchirurgie Acta Chir Austriaca 11 26 137 141 1979 SCHEELE J Klinische Erfahrungen mit der Fibrinklebung an parenchymat sen Oberbauchorganen Akt Chir 17 1982 KALMAR P KREBBER H J POKAR H TILSNER V Bioadhesives in Cardiac and Vascular Surgery Thorac Cardiovasc Surg 30 230 231 1982 HAVERICH A WALTERBUSCH G BORST H G The Use of Fibrin Glue for Sealing Vascular Prostheses of High Porosity Thorac Cardiovasc Surg 29 252 254 1981 BOSCH P NOWOTNY Ch SCHWAGERL W LEBER H ber die Wirkung des Fibrinklebesystems bei orthop dischen Operationen an H mophilen und bei anderen Blutgerinnungsst rungen In Fibrinogen Fibrin und Fibrinkleber Kl Schimpf F K Schattauer Verl 275 277 1980 THETTER O Fibrin Adhesive and its Application in Thoracic Surgery Thorac Cardiovasc Surg 29 290 292 1981 HARTEL W
26. en Local Tolerance s c spongiosa blocks Rabbit TISSEEL s apr frozen Local Tolerance i v paravenous Rabbit Synthetic Aprotinin Human lung Cytotoxicity Lv fibroblasts TISSEEL frozen D x Human lung i Cytotoxicity Lv fibroblasts TISSEEL lyophilized EN Human lung Cytotoxicity Lv fibroblasts TISSEEL s apr frozen Skin Sensitization intradermal epicutan Guinea pig Synthetic Aprotinin Local tolerance studies using a subcutaneously implanted spongiosa block model were conducted with fibrin sealants diluted to a Thrombin concentration of 4 IU mL Page 38 of 41 3 PART III CONSUMER INFORMATION PATIENT COUNSELLING INFORMATION Because this product is made from human plasma the physician should discuss the risks and benefits with the patient Patient should be encouraged to consult with 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 Page 39 of 41 REFERENCES oS 10 11 12 13 14 15 16 17 18 19 B SCH P Die Fibrinspongiosaplastik Wr Klin Wschr 93 Suppl 124 1981 SCHEELE J et al Anastomosensicherung am Verdauungstrakt mit Fibrinkleber In Nahttechnische Grundlagen experimentelle Befunde klinische Erfahrungen Zibl F r Chirurgie 103 1325 1336 1978 GASSER G et al Uber die Verwendung eines Fibrinklebers bei Prostat
27. essure within the pressure range recommended by the spray device manufacturer Do not spray at a pressure above 2 bar or at a distance closer than 10 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 applying TISSEEL using the DuploSpray MIS system connect to regulated CO gas source only maximum input pressure not to exceed 100 psi To avoid possible gas embolism do not directly spray into circulatory pathways Any application of pressurized gas may be associated with a potential risk of gas embolus tissue rupture or gas entrapment with compression which may be life threatening Be sure to take appropriate measures to address these risks by observing the maximum spray pressure of 1 5 bar the recommended minimum spraying distance of 2 cm optional working distance 3 cm and the maximal flow rate of 2 0 standard liters per minute For use by or on order of a licensed physician To reduce the risk of a potentially life threatening gas embolism when applying TISSEEL using a spray device be sure to use a pressure and a distance from tissue with the ranges recommended by the manufacturer in the following table TISSEEL spray application should only be used if it is possible to accurately judge the spray distance Page 8 of 41 Recommended pressure distance and devices for spra
28. etal harm when administered to a pregnant woman Healthcare providers should balance the potential risks and only prescribe TISSEEL if clearly needed See WARNING AND PRECAUTIONS for information on Parvovirus B19 infection Nursing Women 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 a lactating woman Healthcare providers should balance the potential risks and only prescribe TISSEEL if clearly needed Neurosurgical Procedures 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 If fibrin sealants are applied in confined spaces the risk of compressive complications should be taken into account ADVERSE REACTIONS Adverse Drug Reaction Overview Allergic and or anaphylactic reactions may occur in patients with a history of hypersensitivity to Aprotinin Such reactions may be seen in the event of repeated administration even if the first application was well tolerated However allergic and or anaphylactic reactions may also occur in patients receiving TISSEEL for the first time If symptoms require treatment to be initiated this should be effected in the usual manner as for instance with antihistamines corticoids or adrenalin No adverse events of this type were reported duri
29. etic stirrer the vials for freeze dried Sealer Protein Concentrate contain a magnetic spin propeller to stir the contents Heating and stirring can be operated independently In a first step FIBRINOTHERM heats up to 37 C and then maintains that temperature constantly with minimum variation The signal light will turn on and off as FIBRINOTHERM is maintaining its temperature FIBRINOTHERM has been designed to hold the various vial sizes of freeze dried Sealer Protein Concentrate and Aprotinin Solution After plugging the FIBRINOTHERM into an electrical socket and activating the warmer using the amber switch place the Sealer Protein Concentrate and Aprotinin Solution vials from the TISSEEL Kit into prewarmed warming wells with the appropriate sized adaptor ring Refrigerated product may take up to 5 minutes to warm Room temperature product will take less time Transfer Aprotinin Solution into vial containing freeze dried Sealer Protein Concentrate using blue scaled syringe of corresponding size or syringe that has been used for dilution of Aprotinin Solution Note Only combine preheated Aprotinin Solution with preheated Sealer Protein Concentrate Place vial into largest opening of FIBRINOTHERM if necessary use adaptors Turn on stirrer with flip switch and stir contents for 8 10 minutes Reconstitution of freeze dried Sealer Protein Concentrate is complete as soon as no undissolved particles are detectable in transparent light Otherw
30. f the sterile field using an Incubator Incubator 33 C to 37 C 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 and pre filled syringes onto the sterile field Approximate thawing and warming times when using this method are Thawing Warming Times 33 C to 37 C Incubator Pack Size In Pouches 2 mL 40 minutes 4 mL 85 minutes 10 mL 105 minutes NOTE After thawing the product must not be refrigerated refrozen or be exposed to temperatures above 37 C Keep the product at 33 C 37 C until needed The product must be used within 12 hours after warming to 33 C 37 C or removal from original pouches 3 Method of Application Application Considerations See WARNINGS AND PRECAUTIONS General and Application Precautions The use of TISSEEL is restricted to experienced surgeons who have been trained in the use of TISSEEL Page 19 of 41 In open wound surgery the EasySpray pressure regulator that delivers a maximum pressure of no more than 2 0 bar 28 5 psi should be used Avoid spraying closer than 10 cm from the surface of the tissue In minimally invasive laparoscopic procedures use the DuploSpray pressure regulator that delivers a maximum pressure of no more than 1 5 bar 22 psi using only carbon dioxide CO2 gas Observe the recommended minimum spraying distance of 2 cm
31. g orthopedic surgery abdominal surgery urology and cardiovascular surgery The cardiovascular safety study using the heat treated product has shown that TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated transmits neither hepatitis viruses nor HIV Pre clinical studies have shown that the vapor treated product is at least as effective as the heat treated product In the clinical study 550003 described below TISSEEL was shown to be non inferior to an earlier formulation of the product TISSEEL VH predecessor product and both products were shown not to transmit hepatitis HIV or P19B Use of TISSEEL has invariably shown superior results in the groups treated as against the untreated controls who underwent the same types of surgery These results were attributable to an improved hemostasis and therefore reduced blood loss a tighter sealing of sutures preventing leakages or a fast and uncomplicated healing of the surgical wound In none of the studies have systemic side effects been seen nor has any product related transmission of viral hepatitis or HIV occurred in any of the patients treated TISSEEL 500 IU Fast Set TISSEEL 500 IU was evaluated in a prospective parallel design randomized 1 1 double blind multicenter clinical study 550003 against an earlier formulation of the product TISSEEL VH in 317 subjects undergoing cardiac surgery requiring cardiopulmonary bypass CPB and median sternotomy Patients we
32. he Frozen presentation Component Amount 1 Sealer Protein Human Aprotinin Solution sterile contains Total protein 96 125 mg mL Factor XIII 0 6 10 U mL Fibrinogen Clottable Protein 72 110 mg mL Plasmafibronectin CIG 2 9 mg mL Plasminogen 40 120 ug mL Aprotinin Solution sterile 3 000 KIU mL 2 Thrombin Human Calcium Chloride Solution sterile contains Thrombin Human 400 625 IU mL Calcium Chloride Solution sterile 36 44 umol mL Development data not tested at the Final Product level One unit corresponds to the amount of Factor XII contained in 1 mL of fresh normal plasma zz 30 Kallidinogenase Inactivator Units KIU correspond to 1 FIP Unit rr One International Unit IU of Thrombin is defined as the activity contained in 0 0853 mg of the First International Standard of Human Thrombin Nonmedicinal ingredients in the Sealer Protein Aprotinin solution are human albumin niacinamide and water for injection WFI Nonmedicinal ingredients in the Thrombin Calcium Chloride solution are human albumin sodium chloride and water for injection WFI Sodium Hydroxide and Hydrochloric Acid are used to adjust the pH in both solutions All plasma units used for manufacture are ALT tested and non reactive in tests for Hbs antigen and antibodies to HCV HIV 1 and HIV 2 Before further processing all individual plasma Page 28 of 41 dona
33. he course of wound healing the Sealant clot is gradually replaced by ingrowing tissue Thrombin is inactivated by the physiological protease inhibitors Calcium Chloride is subjected to the calcium and chloride catabolism of the organism and Aprotinin and its metabolites are eliminated by the kidney Page 36 of 41 TOXICOLOGY The local application of TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated underlines the importance of histological studies for toxicology data Accordingly histologies have been performed on various species in tissues ranging from skin vessels nerves tendons organ tissue to bone In vivo toxicology studies indicated no acute toxicity and normal local tolerance reactions of TISSEEL Frozen with bovine or synthetic Aprotinin in rats and rabbits respectively Furthermore no difference between synthetic and bovine Aprotinin for single dose toxicity after intravenous application could be detected in mice and rats and synthetic Aprotinin was well tolerated in rabbits No skin sensitizing potential of synthetic Aprotinin was shown in a Guinea Pig Maximization Test In vitro no differences were found between TISSEEL 500 IU Frozen with bovine or synthetic Aprotinin and the predecessor product TISSEEL VH 500 IU lyophilized Kit with respect to cellular compatibility or mutagenicity Synthetic Aprotinin was non mutagenic using an Ames test Cellular compatibility was confirmed in an addition
34. in post marketing experience with Baxter Fibrin Sealants Immune system disorders Anaphylactic responses hypersensitivity manifestations include bradycardia tachycardia hypotension flushing bronchospasm wheezing dyspnea nausea urticaria angioedema pruritus erythema paresthesia anaphylactic reactions including anaphylactic shock have included fatal outcomes Cardiac disorders Bradycardia tachycardia Vascular disorders Hypotension Hematoma embolism arterial including cerebral artery embolism cerebral infarction air embolism as aresult of intravascular application into the superior petrosal sinus as with other fibrin sealants life threatening fatal air or gas embolism has occurred when using devices with pressurized air or gas this event appears to be related to an inappropriate use of the spray device e g at higher than recommended pressure and in close proximity to the tissue surface Page 12 of 41 Respiratory thoracic and mediastinal disorders Dyspnea Gastrointestinal disorders Nausea intestinal obstruction Skin and subcutaneous tissue disorders Urticaria General disorders and administration site conditions Flushing impaired healing oedema pyrexia Injury poisoning and procedural complication Seroma There have been rare reports of serious adverse events such as paralysis and other compressive complications possibly related to the use of fibrin seala
35. inistration of TISSEEL TISSEEL with the EasySpray Set must not be used in enclosed body areas 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 The EASYSPRAY control device DuploSpray MIS Surgical Sealant Delivery System and the Spray Set may be obtained from Baxter To prevent TISSEEL from adhering to gloves and instruments wet these with saline before contact with Sealant Page 7 of 41 To avoid the formation of excess granulation tissue and to ensure gradual absorption of the solidified fibrin sealant only a thin layer of TISSEEL should be applied see Application Precautions and OVERDOSAGE 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 Separate sequential application of the two components must be avoided Application Precautions Only a thin layer of TISSEEL should be applied Excessive thickness of the fibrin sealant layer may interfere with the products efficacy and the wound healing process It is strongly recommended that every time TISSEEL is applied to a patient the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product When applying TISSEEL using the EASYSPRAY device be sure to use the pr
36. ise replace into FIBRINOTHERM and agitate for another few minutes until the solution appears homogeneous Note Excessive stirring 20 minutes or more may compromise product quality Note Keep the Sealer Protein Solution at 37 C or at room temperature without stirring if it is not to be used immediately Before use the solution should be warmed to 37 C To ensure homogeneity stir or swirl briefly before aseptically drawing up the Sealer Protein Solution into the blue scaled syringe provided in DUPLOJECT System ii Reconstitution of Freeze Dried Sealer Protein Concentrate Using a Water Bath Note When using a water bath for reconstitution special precautions must be taken against submerging the vial particularly the septum to avoid possible contamination Page 16 of 41 Preheat the vials containing the Sealer Protein Concentrate lyophilized and the Aprotinin Solution for approximately 3 minutes in a water bath at a temperature of 33 C to 37 C Heating beyond 37 C must be avoided Remove the flip off caps from the vial containing freeze dried Sealer Protein Concentrate and the vial containing Aprotinin Solution disinfect the rubber stoppers of both vials with a germicidal solution and allow to dry Do not use iodine containing preparations such as betadine for disinfection Transfer Aprotinin Solution into vial containing freeze dried Sealer Protein Concentrate using blue scaled syringe of corresponding size or syringe
37. lcium Chloride Solution syringe chamber 2 Sealer Protein Concentrate Human Sealer Protein Aprotinin Solution Aprotinin Solution Synthetic Thrombin Human Thrombin Calcium Calcium Chloride Solution Chloride Solution The two components are mixed either immediately before application to the recipient surface or in situ using one of the methods described under Method of Application The Sealer Protein Thrombin Solution after mixing is a viscous solution adhering to wound surfaces and quickly sets to form a white rubberlike mass which continues to gain in strength within two hours following application This process is made use of to achieve hemostasis and to seal or glue tissue TISSEEL Fibrin Sealant In this manner the need for sutures may be reduced although not totally eliminated The time until Sealant sets can be used to approximate wound edges to provide optimum conditions for healing In the course of wound healing Sealant is completely absorbed Page 34 of 41 Fibrin Sealant is a two component biological sealant produced from pooled human plasma As for all plasma products the following measures are implemented to ensure the safety of the product from the potential presence of pathogenic viruses in human plasma e Donor selection e Donation testing of single donations and also at the mini pool and manufacturing pool level e The use of PCR assay system PCR for release of plasma pools e Effective
38. lvent Detergent Treatment gt 5 3 n d gt 5 5 gt 6 4 n d n d Ion Exchange Chromatography n d n d n d n d 3 6 n d Overall Reduction Factor ORF gt 14 0 gt 6 4 gt 12 6 gt 15 6 5 8 gt 5 7 n d not determined The mean RF of all runs was calculated E g when two runs were performed in study A and one run in study B for HIV 1 then the mean of the three RF s was calculated and listed in the table As a conservative value for general and robust Parvovirus reduction capacity in steps 1 to 8 2 3 logs were calculated from MMV and B19V reduction factors omitting the higher B19V reduction factor For calculation of and rationale behind this value see further above in the section where the corresponding study is discussed For calculation of virus specific overall reduction factors however only virus specific individual reduction factors were considered 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 enveloped DNA viruses among those Hepatitis B virus MMV Mice minute virus a model for Human Parvovirus B19 B19V Human Parvovirus B19 Page 31 of 41 CLINICAL TRIALS Numerous clinical studies investigating the safety and efficacy of the product as a hemostyptic and biodegradable tissue glue in various fields of surgery have been performed A number of these were controlled studies in fields includin
39. nds on the concentration of the human Thrombin as contained in the Thrombin Calcium Chloride Solution used The TISSEEL thrombin component is provided in a 500 IU mL concentration TISSEEL 500 IU Fast Set Time to clot formation polymerisation commences within seconds with a Thrombin concentration of 500 IU mL Therefore TISSEEL 500 IU Fast Set is indicated to be used to achieve rapid setting e g for hemostasis Sealer Protein Human and Thrombin Human are made from pooled human plasma The vapor heat and solvent detergent treatment steps used in the manufacturing process have been shown to be capable of significant viral reduction Despite this when medicinal products prepared from human blood or plasma are administered the possibility of transmitting infective agents cannot be totally excluded see WARNINGS AND PRECAUTIONS and PHARMACEUTICAL INFORMATION and see DOSAGE FORMS COMPOSITION AND PACKAGING for available package sizes and presentations INDICATIONS AND CLINICAL USE TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated is used in addition to standard measures to achieve hemostasis to seal or glue tissue and to support wound healing Indications include 2 6 7 abdominal surgery 4 5 8 9 cardiovascular surgery 1 1 orthopedic surgery thoracic surgery Se 3 14 15 16 urology Page 4 of 41 Geriatrics gt 65 years of age Efficacy and safety in use of Fibrin Sealant h
40. ng the clinical trials for TISSEEL Clinical Trial Adverse Drug Reactions ADRs Because clinical trials are conducted under widely varying conditions adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice Page 10 of 41 TISSEEL 500 IU Fast Set The following ADRs have been reported from three clinical trials None of the events was classified as serious During a clinical study in cardiovascular surgery where 157 patients were treated with TISSEEL 500 IU Fast Set two cases of increased Fibrin D Dimer levels were observed 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 see Part II Clinical Trials trial number 550003 In a study in axillary lymph node dissection where 79 patients were treated with TISSEEL 500 IU Fast Set the most frequently occurring ADRs were seroma 13 cases and pain in limb 4 cases However the overall incidence of related and unrelated seroma and procedural pain was comparable between the TISSEEL 500 IU Fast Set and an untreated control group 21 5 vs 18 3 in this study Other adverse events reported were 2 cases each of nausea post operative wound infection and post procedural pain and 1 case each of pain increase of body temperature increase of fibrin degradation products sensory disturbance rash
41. nt in combination with resorbable hemostatic agents Manifestations of hypersensitivity or allergic reactions include application site irritation chest discomfort chills headache lethargy restlessness and vomiting There have also been rare reports of fatalities following the misadministration of topical thrombin Because these reactions are reported voluntarily and the population is of uncertain size it is not always possible to reliably estimate the frequency of these reactions DRUG INTERACTIONS Overview No formal interaction studies have been performed Drug interactions are not known TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated can even be applied in fully heparinised patients e g extracorporeal circulation Incompatibilities Solutions containing alcohol iodine or heavy metals will interfere with the product s performance due to denaturation of proteins or other mechanisms If any of these substances have been used to clean the wound area the area must be thoroughly rinsed before application of None known based upon the absence of data from clinical trials current medical scientific literature and safety reports Page 13 of 41 TISSEEL Oxidized cellulose containing preparations may reduce the efficacy of TISSEEL by inactivating thrombin and should not be used as carrier materials TISSEEL must not be mixed with other medicinal products DOSAGE AND ADMINISTRATION T
42. oduct from the surgical site Mild reactions can be managed with antihistamines Severe hypotensive reactions require immediate intervention using current principles of shock therapy Adequate medical treatment and provisions should be available for immediate use in the event of an anaphylactic reaction Caution must be used when applying fibrin sealant using pressurized air or gas See DOSAGE AND ADMINISTRATION Life threatening fatal air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer TISSEEL 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 The risk appears to be higher when fibrin sealants are sprayed with air as compared to CO and therefore cannot be excluded when TISSEEL is used in open wound surgery Solutions containing alcohol iodine or heavy metals will interfere with the product s performance due to denaturation of proteins or other mechanisms Page 6 of 41 General Fibrin Sealant is made from human plasma Products made from human plasma may contain infectious agents such as viruses that can cause disease This also applies to unknown or emerging viruses and other pathogens The risk that such products will transmit an infectious agent has been reduced by screening plasma and by inactivating and removing certain viruses Despite these measures there may still carry a ri
43. on of Aprotinin in the product formulation increases resistance of the fibrin sealant clot to degradation in a fibrinolytic environment Pharmacokinetics TISSEEL is intended for local application only therefore systemic exposure or distribution to other organs or tissues is not expected and pharmacokinetic studies were not conducted STORAGE AND STABILITY TISSEEL Kit Freeze Dried When stored between 2 C and 25 C 36 F and 77 F TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated Kit lyophilized is stable until the expiry date indicated on the label Do not freeze After reconstitution the product must be used within 4 hours Reconstituted solutions must not be refrigerated or frozen Page 26 of 41 TISSEEL Pre filled Syringe Frozen When stored at lt 20 C lt 4 F TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated Frozen in pre filled syringes is stable until the expiry date indicated on the label Room Temperature Storage Unopened pouches thawed at room temperature may be stored for up to 7 days at room temperature 15 C 25 C after removal from the freezer DOSAGE FORMS COMPOSITION AND PACKAGING Dosage Forms and Packaging TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated is available in two different dosage forms Kit and Frozen Strength Volume Kit Frozen Total One vial lyophilized Sealer Protein 1 0 mL
44. or when using an endoscope or trocar TISSEEL can be applied using DUPLOCATH Application Catheters Note For operation instructions please refer to the Instructions for Use provided together with DUPLOCATH Application Catheter 25 35 or 180 In case of using other accessories provided by Baxter please refer to the operating instructions contained in the Instructions for Use for the particular accessory d Simultaneous Application by Premixing Mix equal volumes of the two components and immediately apply them to the recipient surface or surfaces If desired the Thrombin Solution can be mixed with spongiosa to pack bone defects Hold in place for three minutes Once turbid TISSEEL can no longer be manipulated e Simultaneous Application Using DuploSpray MIS Surgical Sealant Delivery System The DuploSpray MIS applicator is intended for the application of TISSEEL Fibrin Sealant The applicator consists of a rigid and sterile stainless steel cannula dual lumen spray tubing sterile filter and two replacement spray tips It delivers a thin uniform film of fibrin sealant over wound surfaces for maximum product utilization and broad area coverage The regulator is a pressure regulating device for the control and release of compressed gas from a pressurized CO source this is the safest gas to use in laparoscopic procedures and with a patient vent line provides pressure stability during application The gas assisted applicator mixes and
45. product A Fibrinolysis Inhibitor Aprotinin is included in the Sealer Protein Human component to preclude premature fibrinolysis To obtain Sealer Protein Concentrate Page 3 of 41 Human cryoprecipitate derived from the plasma is dissolved in buffer solution solvent detergent treated purified by precipitation and washing steps vapor heat treated formulated sterile filtered and either freeze dried in vials or concentrated under vacuum and 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 liquid Thrombin Calcium Chloride Solution pre filled into one side of a double chamber syringe chamber containing Thrombin Calcium Chloride solution is marked as 2 The active ingredient human 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 purification by ion exchange chromatography formulation sterile filtration and either freeze drying in vials or filling and freezing in pre filled syringes The setting rate of the Fibrin Sealant depe
46. re treated with TISSEEL 500 IU 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 500 IU was at least as effective as the earlier formulation of the product using a one sided 97 5 confidence interval on the difference in the proportion of subjects successfully treated Hemostasis within 5 minutes and maintained until surgical closure TISSEEL 500 IU Predecessor product 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 Page 32 of 41 Geriatrics gt 65 years of age In this Phase 3 clinical study of TISSEEL 500 IU 71 of 144 subjects were 65 and over 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 An earlier formulation of TISSEEL s predecessor product TISSEEL HT heat treated containing bovine thrombin 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 HT or control hemostatic agents when a topical
47. rile Disposable DUPLOSPRAY MIS Propellant gas control unit with 20 cm 30 cm and 40 cm applicators and SURGICAL tips for the application of surgical sealant SEALANT DELIVERY SYSTEM DuploTip Catheter double canal Dual Lumen Cannula Length 10 4 cm or 32 cm Alternative reconstitution accessories are available for TISSEEL Page 29 of 41 2 PART II SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance See PART I DESCRIPTION and PART II DETAILED PHARMACOLOGY Sections Product Characteristics See PART I DESCRIPTION and PART II DETAILED PHARMACOLOGY Sections Viral Inactivation TISSEEL Fibrin Sealant Human Vapor Heated Solvent Detergent Treated 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 see Detailed Pharmacology by testing for the presence of certain current virus infections and by inactivating and removing certain viruses in the course of the manufacture 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 In addition the reduction facto
48. rs as associated with DEAE Sephadex Batch Chromatography and Ion Exchange Chromatography of the Thrombin drug substance purification were investigated 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 log o of independent manufacturing steps were as follows for each of the viruses tested Page 30 of 41 Reduction Factors for Virus Removal and or Inactivation Sealer Protein Component Mean Reduction Factors log o of Virus Tested Manufacturing Step HIV 1 HAV BVDV PRV MMV B19V DEE 3 4 Early Manufacturing Steps n d n d n d n d ERC Solvent Detergent Treatment gt 5 3 n d gt 5 7 gt 5 9 n d n d Vapor Heat Treatment gt 5 5 gt 5 6 gt 5 7 gt 6 7 1 2 1 0 Overall Reduction Factor ORF gt 10 8 gt 5 6 gt 11 4 gt 12 6 3 5 3 3 Reduction Factors for Virus Removal and or Inactivation Thrombin Component Mean Reduction Factors logo of Virus Tested Manufacturing Step HIV 1 HAV BVDV PRV MMV B19V Removal of Thrombin precursor 32 15 18 25 12 L7 protein from Cryosupernatant Vapor Heat Treatment gt 5 5 gt 4 9 gt 5 3 gt 6 7 1 0 gt 4 So
49. sk of intravascular application However if in well founded cases the injection of TISSEEL and or Thrombin Solution s into a tissue or vessel is proposed careful risk benefit analysis of the individual case is required As with any other protein products hypersensitivity or allergic anaphylactic anaphylactoid reactions may occur with the use of TISSEEL a fibrin sealant that contains aprotinin In isolated cases these reactions have progressed to severe anaphylaxis Aprotinin a monomeric polypeptide is known to be associated with anaphylactic reactions These reactions may also occur in patients receiving Aprotinin or TISSEEL for the first time or even if first application was well tolerated but generally risk may be increased if the preparation is applied repeatedly over time or in the same setting Manifestations of hypersensitivity reactions to TISSEEL observed include flush urticaria pruritus nausea drop in blood pressure tachycardia or bradycardia dyspnea severe hypotension bronchospasm wheezing angioedema erythema paresthesia Fatal anaphylactic reactions including anaphylactic shock have also been reported with TISSEEL see ADVERSE REACTIONS As with other aprotinin containing products the use of TISSEEL should be documented in the patient s records pointing out that TISSEEL contains aprotinin In the event of hypersensitivity reactions administration of TISSEEL is to be discontinued Remove any applied polymerized pr
50. sk of transmitting infectious agents e g viruses and theoretically the Creutzfeldt Jakob disease CJD agent The standard measures taken including double virus inactivation by vapor heat treatment and solvent detergent treatment are considered effective for enveloped viruses such as HIV HBV and HCV and for the non enveloped virus HAV 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 and individuals with immunodeficiency or increased red blood cell turnover In the submucous injection of fibrin sealant into hollow organs to stop GI bleeding stomach duodenum the following points are to be considered e Insertion of the needle into the organ wall may result in accidental perforation which in rare cases may injure adjoining organs or vessels e Injection into the submucous membrane may cause a mechanical dissection between the tunica mucosa and the tunica muscularis propria which in rare cases may lead to vessel injury or the formation of an intramural hematoma e Injection into the nasal mucosa must be avoided as severe allergic anaphylactoid reactions have been seen and thromboembolic events may occur This product must not be used in animals The user is cautioned against the spray application of TISSEEL with devices produced by other manufacturers Only use application devices licensed for the adm
51. the application cannula and ejected Application Canula JE Joining piece Operating Instructions DUPLOJECT Two Syringe Clip Place the two syringes filled with Sealer Protein Solution and with Thrombin Solution into the clip Both syringes should be filled with equal volumes Connect the nozzles of the two syringes to the joining piece ensuring that they are firmly fixed Secure the joining piece by fastening the tether strap to the DUPLOJECT Two Syringe Clip Should the pull strap tear use the spare joining piece If none is available further use is still possible but tightness of the connection needs to be ensured to prevent any risk of leaking Fit an application cannula onto the joining piece Page 21 of 41 Do not expel the air remaining inside the joining piece or application cannula until you start actual application as the aperture of the cannula may clog otherwise Apply the mixed Sealer Protein Thrombin Solution onto the recipient surface or surfaces of the parts to be sealed If application of the fibrin sealant components is interrupted clogging may occur in the cannula To resume application replace the application cannula with a new one If the apertures of the joining piece are clogged use the spare joining piece provided in the DUPLOJECT System Note For operation instructions please refer to the Instructions for Use provided together with the DUPLOJECT System ii Administration using DUO Set
52. tions are subjected to an inventory hold for a possible look back of plasma donations suspected of infection All plasma units are tested by HIQ PCR Hyland Immuno Quality Assured Polymerase Chain Reaction ACCESSORIES The following are some accessories for use with TISSEEL VH S D A complete list of accessories can be obtained from a Baxter representative When using these devices strictly follow the Instructions for Use of the devices FIBRINOTHERM Combined Heating and Stirring Device EASYSPRAY Propellant gas control unit manometer reducing valve and pressure tube Spray Set sterile Disposable set consisting of sterile filter with connection tube sensing disposable line and a spray head DUPLOCATH 25 Length approximately 25 cm 10 Application Catheter Diameter approximately 5 french approx 0 17 cm Radiopaque Sterile Disposable DUPLOCATH 35 Catheter M LS Application Catheter DUPLOCATH 180 Length approximately 35 cm 14 Diameter approximately 5 french approx 0 17 cm Adapter Length approximately 30 cm 12 Diameter 15 french 0 5 cm For insertion through a 5 6 mm trocar in minimally invasive surgery M LS Radiopaque Sterile Disposable Length approximately 180 cm 70 Application Catheter Diameter approximately 5 french approx 0 17 cm For use with an endoscope The Application Catheter 180 can be shortened to any length necessary Radiopaque Ste
53. virus inactivation removal steps integrated into the manufacturing process including validation Each plasma donation is tested for infectious markers for human immunodeficiency virus types 1 and 2 HIV 1 2 hepatitis C virus HCV and hepatitis B surface antigen HbsAg The criteria for release of each single plasma donation for further manufacturing are as follows e HIV 1 HIV 2 antibody non reactive e HbsAg non reactive e HCV antibody non reactive Each manufacturing plasma pool is tested and released for further manufacturing only when e non reactive for Human Immunodeficiency Virus HIV Hepatitis C Virus HCV Hepatitis A Virus HAV and Hepatitis B Virus HBV using Nucleic Acid Testing NAT e Parvovirus B19 concentration not exceeding 10 IU mL as measured by NAT Plasma pool are tested using HIQ PCR Hyland Immuno Quality Assured Polymerase Chain Reaction With the PCR method in general 500 genome equivalents mL of the above viruses can be determined reliably with the actual sensitivity of HIQ PCR being below that Therefore all pools which have been tested and evaluated as being positive lead to exclusion from further processing The plasma safety precautions and virus inactivation removal steps taken during the manufacture of TISSEEL VH S D 500 IU are equivalent to those used for ARTISS 4 IU During the pivotal clinical study of TISSEEL VH S D 500 IU Fibrin Sealant there were zero confirmed seroconversions for HAV HBV
54. y application of TISSEEL Spray set to be Applicator Pressure Recommended Rasse Surgery tips to be regulator to distance from used Spray Pressure used be used target tissue Tisseel Artiss n a EasySpray Spray Set Pressure Regulator 1 5 2 0 bar aan Tisseel Artiss n a EasySpray a 21 5 28 5 psi Spray set 10 pack Pressure Regulator DuploSpray DuploSpray MIS MIS Applicator Regulator 20 cm DuploSpray DuploSpray MIS MIS Laparoscopic Applicator Regulator a n a 2 2 5 cm 1 2 1 5 bar invasive DuploSpray DuploSpray 18 22 psi procedures MIS MIS Applicator Regulator 40 cm Replaceable DuploSpray Tip MIS Regulator Solutions containing alcohol iodine or heavy metals will interfere with the product s performance due to denaturation of proteins or other mechanisms If any of these substances have been used to clean the wound area the area must be thoroughly rinsed before application of TISSEEL Cardiovascular In coronary bypass surgery TISSEEL should be applied with caution to minimize any risk of intravascular application Sexual Function Reproduction Animal reproduction studies have not been conducted with TISSEEL It is also not known whether it can affect reproduction capacity Page 9 of 41 Special Populations Pregnant Women No experience Animal reproduction studies have not been conducted with TISSEEL It is also not known whether it can cause f
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