Thursday, September 8, 2016

Tisseel Kit





1. Name Of The Medicinal Product



TISSEEL KIT


2. Qualitative And Quantitative Composition



Each TISSEEL Kit contains 4 vials. The active ingredients are:



TISSEEL Powder for Sealer Protein Solution, Human, Vapour Heated



After reconstitution of the powder, 1 ml of TISSEEL Solution contains:



Total protein 100 - 130 mg of which 75 - 115 mg is Fibrinogen.



Aprotinin Solution, Solvent for TISSEEL Powder



Aprotinin, bovine 3000 KIU1/ml



Thrombin Powder for Thrombin Solution, Human, Vapour Heated



After reconstitution of the powder, 1 ml of Thrombin Solution contains:



500 IU2 of Thrombin in 45-55 mg of Total protein.



Calcium Chloride Solution, Solvent for Thrombin Powder



Ca2+ 40 µmol/ml



3. Pharmaceutical Form



Powders and solvents for fibrin sealant.



One TISSEEL KIT contains all the substances required for the preparation of the two fibrin sealant components and the kit for reconstitution and application (for details see Section 6.5. Nature and Contents of Containers).



4. Clinical Particulars



4.1 Therapeutic Indications



Tisseel is intended to complement good surgical technique in achieving haemostasis, or obtaining a watertight seal of the dura mater.



TISSEEL KIT is used as an adjunct to haemostasis in cardiopulmonary bypass surgery when control of bleeding by conventional surgical techniques including sutures, ligatures, and cautery is considered ineffective or impractical. Tisseel Kit is used as an adjunct to dural sealing when control of cerebrospinal fluid (CSF) leakage by conventional neurosurgical techniques including sutures and patches is considered insufficient or impractical.



4.2 Posology And Method Of Administration



4.2.1 Posology



The required dose of TISSEEL Solution depends on the size of the surface to be covered. It is also dependent on the application method chosen.



As a guideline for the covering of surfaces one TISSEEL KIT 1.0 (i.e. 1 ml TISSEEL Solution plus 1 ml Thrombin Solution) will be sufficient for an area of at least 10 cm².



When the fibrin sealant is applied by spray application the same quantity will be sufficient to coat an area of 25 cm² to 100 cm², depending on the individual case.



To avoid undue pressure on the brain, spinal cord and/or cranial or spinal nerves, formation of excess granulation tissue and to ensure gradual absorption of the solidified fibrin sealant, only a thin layer of the TISSEEL-Thrombin Solution, or the individual components, should be applied.



To obtain an air and watertight seal, Tisseel must be applied directly to the site of dural incontinuity and/or along the dura sutures in a thin, even layer. Tisseel Fibrin Sealant alone can withstand high hydrostatic pressure. However, since the sealant may be resorbed after seven days, it must be used in conjunction with dural, muscle or fat graft, or a collagen fleece.



Gradual absorption of TISSEEL Sealant is desirable as wound healing progresses. To prevent premature lysis, however, absorption is slowed down by the addition of aprotinin, a natural protease inhibitor, and so the TISSEEL Powder is reconstituted with Aprotinin Solution (3000 KIU/ml).



As soon as TISSEEL Solution is mixed with Thrombin Solution the setting process starts. Due to the high thrombin concentration of 500 IU/ml a fibrin clot forms within a few seconds.



4.2.2 Methods of Administration



The fibrin sealant components can be applied by the following methods:



I) Simultaneous Application



− using the DUPLOJECT Two-Syringe Clip, Joining Piece, and Application Needle



− using the DUPLOJECT Two-Syringe Clip, Spray Set, and TISSOMAT Propellant Gas Control Unit



− using the DUPLOJECT Two-Syringe Clip and DUPLOCATH Application Catheter



II) Sequential Application



I. Simultaneous Application



The DUPLOJECT Two-Syringe Clip allows simultaneous application of equal quantities of TISSEEL Solution and Thrombin Solution so that the two components are quickly and thoroughly mixed. This is essential for TISSEEL fibrin sealant to gain optimum strength.



a) Simultaneous Application Using the DUPLOJECT Two-Syringe Clip, Joining Piece, and Application Needle:





The DUPLOJECT Two-Syringe Clip holds two identical disposable syringes and has a common plunger which ensures that equal volumes of the two components are fed through a common Joining Piece before being mixed in the Application Needle and ejected.



Operating Instructions



– Place the two syringes filled with TISSEEL Solution and Thrombin Solution into the clip. Make sure that both syringes are filled with equal volumes. Any major air bubbles should be removed.



– Firmly attach the Joining Piece to the nozzles of the two syringes. Tighten the pull strap and fasten it to the attachment point on 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 ensure the tightness of the connection to prevent any risk of leaking.



– Fit an Application Needle onto the Joining Piece.



Do not expel the air remaining inside the Joining Piece or Application Needle until you start actual application.



– Apply the TISSEEL-Thrombin Solution onto the recipient surface or surfaces of the parts to be sealed.



If application of the fibrin sealant components is interrupted, clogging occurs immediately in the needle. Only replace the Application Needle immediately before sealing is to be resumed. If the Joining Piece becomes clogged use the spare Joining Piece provided.





b) Simultaneous Application Using the DUPLOJECT Two-Syringe Clip, Spray Set and TISSOMAT Propellant Gas Control Unit:



In the management of extensive wound areas - for example the arrest of oozing haemorrhage - TISSEEL Solution and Thrombin Solution can be applied with this device combination.



The Spray Head is attached to the two syringe tips. By pressing the common plunger the two solutions are passed to two adjacent outlets which are encircled by the pressure gas exit. The gas flow atomises and mixes the two components which can then be sprayed simultaneously using sterile propellant gas (compressed air, nitrogen or CO2; pressure: approx. 2-3 bar, 5-10 l/min). The volume of the solutions ejected is controlled by the DUPLOJECT plunger. The pressure and flow rate of the propellant gas are controlled with the TISSOMAT Propellant Gas Control Unit. The Spray Set must be used only in connection with the TISSOMAT Propellant Gas Control Unit.



The user is cautioned against the spray application of TISSEEL Solution and Thrombin Solution with devices produced by other manufacturers.



Note: A detailed description of this application method is included in the leaflet of the Spray Set.



c) Simultaneous Application Using the DUPLOJECT Two-Syringe Clip and DUPLOCATH Application Catheters:



In operation sites where access is difficult TISSEEL Solution and Thrombin Solution can be applied using this approach.



II. Sequential Application



For this method of application the two syringes are used separately.



Apply TISSEEL Solution to one of the surfaces to be sealed and an equal quantity of Thrombin Solution to the other; then join the two surfaces. The rapid solidification of the fibrin sealant leaves very little time for approximation and adaptation of the surfaces.



Note: Regardless of the application method chosen, allow for about 3–5 minutes of undisturbed solidification after application to ensure that the setting fibrin sealant adheres firmly to the surrounding tissue. To this end, hold the sealed parts together with continuous gentle pressure in the desired position. Avoid any manipulation of the sealed surface during this period.



In certain applications biocompatible material, such as collagen fleece, is used as a carrier substance or for reinforcement.



Solidified TISSEEL Sealant reaches its maximum strength after about 2 hours (70% after about 10 minutes).



To prevent fibrin sealant from adhering to gloves and instruments, wet these with saline before contact.



TISSEEL Sealant adhering to tissue outside the wound area should be removed (for example with a surgical knife). TISSEEL Sealant is easily identified by its whitish colour.



4.3 Contraindications



TISSEEL must not be applied intravascularly.



Known hypersensitivity against aprotinin or any other ingredients.



Tisseel Kit is not indicated for the treatment of arterial bleeding.



Injection into the nasal mucosa must be avoided, as severe allergic-anaphylactoid reactions have been observed and thromboembolic complications may occur in the area of the ophthalmic artery.



4.4 Special Warnings And Precautions For Use



4.4.1 Precautions



1. For patients with known allergic diathesis, or known hypersensitivity to medicinal products, and for patients having previously received aprotinin, careful risk/benefit assessment must be carried out. It is recommended that antihistamines should be administered to these patients prior to aprotinin application.



2. Injection of TISSEEL and/or Thrombin Solution carries a risk of anaphylactoid reactions. Intravascular and intraventricular administration carries the additional risk of a thromboembolic complication. Both complications may be life threatening. Therefore, care should be taken to ensure that TISSEEL and/or Thrombin Solution are only applied topically (See Section 4.3).



3. Fibrin Sealant may be applied as a spray using pressurised gas. Any application of pressurised gas may be associated with the risk of air embolism, gas emphysema, or tissue or organ rupture, which may be life threatening. Consequently spray application of fibrin sealant should not be carried out in enclosed body areas. The spraying of fibrin sealant should only be carried out under visual control using the TISSOMAT Propellant Gas control unit at a distance no nearer than 10 cm from the surface to be sealed.



4. The spray application for dura sealing should not be carried out in intradural sealing and reconstruction procedures or in cortical dural sealing procedure in cases in which the cerebral ventricular system was opened. This may be associated with a tensile pneuomocephalus, which is life threatening.



5. The user is cautioned against the spray application of TISSEEL Solution and Thrombin Solution with devices provided by other manufacturers. The TISSOMAT Propellant Gas Control Unit and the Spray Set are available from Baxter Healthcare Ltd.



6. Similarly to comparable products or thrombin solutions, TISSEEL may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed to the greatest possible extent before applying the sealant.



7. To prevent unnecessary application to areas adjacent to the surface to be sealed, if possible, cover all tissue adjacent to the site of sealing before applying TISSEEL and Thrombin Solutions.



8. As with any protein product, allergic type hypersensitivity reactions are possible. Signs of hypersensitivity reactions include hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the administration has to be discontinued immediately.



9. TISSEEL contains bovine protein (aprotinin). Even in the case of strict local application there is a risk of anaphylactic reaction, linked to the presence of bovine aprotinin. The risk seems higher in case of previous exposure even if it was well tolerated. Therefore, any use of aprotinin, or aprotinin-containing products, should be recorded in the patients' records.



10. It is strongly recommended that every time TISSEEL is administered to a patient, the name and batch number of the product are recorded.



11. In case of shock, current medical standards for shock treatment should be observed.



4.4.2. Warnings



TISSEEL Powder and Thrombin Powder are made from human plasma originating from plasma and whole blood collected in licensed plasmapheresis centres, blood donation centres and transfusion services across the USA and some European countries excluding the UK. Blood/plasma donations are not collected in countries where clusters of cases of nvCJD are known.



Each initial plasma pool consists of a maximum of 1660 l plasma corresponding to approximately 2100 individual donations. When medicinal products prepared from human blood or plasma are administered, infectious diseases due to the transmission of infective agents cannot be totally excluded. This also applies to pathogens of hitherto unknown nature. To reduce the risk of transmission, selection of donors and donations by suitable measures (screening plasma donors for prior exposure to certain viruses, testing donations for the presence of certain current virus infections) is performed and plasma pools are tested for viruses and viral markers. In addition, the human plasma derived components are subjected to an efficient virus inactivation process by vapour heating during the manufacturing process.



In order to minimise the risk, the following measures have been implemented: Plasma pool testing for virus genome sequences of HIV-1 and-2, HBV and HCV with the polymerase chain reaction (HIQ-PCR) 3, Non-Returning Donor-Applicant Exclusion, Inventory Hold and the Lookback Programme.



The removal/inactivation procedures used may be of limited value against parvovirus B19 and hitherto unknown viruses. The possibility of parvovirus B19 transmission must be considered particularly for immunodeficient patients and seronegative pregnant women, since they may be more severely affected.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



No formal interaction studies have been performed.



Similar to comparable products or thrombin solutions, TISSEEL may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed to the greatest possible extent before applying the sealant.



The sealant may even be applied in fully heparinised patients (e.g. extracorporeal circulation).



4.6 Pregnancy And Lactation



No undesirable effects are known to occur associated with the application of TISSEEL during pregnancy or lactation. In line with generally recognised recommendations, medicinal products should be given during pregnancy or lactation only when strictly indicated.



4.7 Effects On Ability To Drive And Use Machines



Not applicable.



4.8 Undesirable Effects



Inadvertent intravascular and intraventricular administration carries the risk of thromboembolic complications. Therefore, care should be taken to ensure that TISSEEL and/or Thrombin solution is only applied topically.



Injection of TISSEEL and/or Thrombin solution carries a risk of anaphylactoid reactions. Anaphylactic or anaphylactoid reactions may occur following the repeated administration of TISSEEL, the systemic administration of aprotinin and in patients with known hypersensitivity to aprotinin. In these circumstances, prophylactic premedication with H1 antagonists should be given. Rarely, allergic reactions may occur in patients receiving TISSEEL or aprotinin for the first time. Symptoms associated with allergic reactions include the following: flushing, urticaria, pruritus, nausea, hypotension (which may be severe), tachycardia or bradycardia and dyspnoea. In the event of a hypersensitivity reaction occurring, the administration of TISSEEL should be immediately discontinued and appropriate emergency measures taken.



Both anaphylactoid reactions and thromboembolic complications may be life threatening.



4.9 Overdose



No data are available concerning overdose with TISSEEL.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic Classification



Blood and blood forming organs / antihaemorrhagics / vitamin K and other haemostatics / local haemostatics



ATC code BO2BC



The fibrin adhesion system initiates the last phase of physiological blood coagulation. Conversion of fibrinogen to fibrin occurs by the splitting of fibrinogen into fibrin monomers and fibrinopeptides. The fibrin monomers aggregate and form a fibrin clot. Factor XIIIa, which is activated from factor XIII by thrombin, crosslinks fibrin.



Calcium ions are required for both the conversion of fibrinogen and the crosslinkage of fibrin.



As wound healing progresses, increased fibrinolytic activity is induced by plasmin and decomposition of fibrin to fibrin-degradation products is initiated. Proteolytic degradation of fibrin is inhibited by aprotinin.



TISSEEL Kit is a biological two-component sealant. The components (TISSEEL Solution and Thrombin Solution) are mixed during or immediately before application (see 4.2.2. Methods of Administration). This results in a viscous TISSEEL-Thrombin Solution that quickly sets to form a white mass (TISSEEL Sealant), which firmly adheres to tissue. This process simulates the key features of the physiological coagulation process and is used to achieve haemostasis.



The process is illustrated by the following diagram:





5.2 Pharmacokinetic Properties



When the fibrin sealant components come into contact, polymerisation (fibrinogen to fibrin conversion and fibrin cross linking) starts immediately and results in the setting of the fibrin sealant within seconds.



The solidified fibrin sealant is completely absorbed in the course of wound healing.



The degradation and absorption of solidified fibrin sealant is triggered at the interface between the sealant and tissue by cells which migrate into the sealant clot, where they develop fibrinolytic activity.



The plasma proteins present in TISSEEL Kit are eliminated at the same rate as the autologous plasma proteins. Thrombin is partly adsorbed by the fibrin formed. Excess thrombin, if any, is inactivated by protease inhibitors present in blood. Released aprotinin and its metabolites are eliminated by the kidney. Its half-life in blood is known to average between 30 and 60 minutes.



5.3 Preclinical Safety Data



No preclinical safety data are available for TISSEEL Kit on acute toxicity, subacute and chronic toxicity, carcinogenicity or immune stimulation. None of the proteins contained in TISSEEL Kit, nor calcium chloride have mutagenic effects.



Animal studies in rats have not shown any local toxicity.



High doses of aprotinin injected intravenously to pregnant rats had no embryotoxic or teratogenic effect.



6. Pharmaceutical Particulars



6.1 List Of Excipients



6.1.1 Excipients of TISSEEL Powder



Glycine



Human Albumin



Trisodium Citrate



Sodium Chloride



Polysorbate 80



6.1.2 Excipients of the Aprotinin Solution



Water for Injections



6.1.3 Excipients of Thrombin Powder



Human Albumin



Sodium Chloride



Glycine



6.1.4 Excipients of the Calcium Chloride Solution



Water for Injections



6.2 Incompatibilities



TISSEEL and Thrombin Solutions can be denatured following contact with solutions containing alcohol, iodine or heavy metals.



6.3 Shelf Life



TISSEEL Kit has a shelf life of 2 years. Do not use after the expiry date.



Chemical and physical in-use stability of reconstituted TISSEEL and Thrombin Solutions has been demonstrated for 6 hours at room temperature up to 37°C (reconstituted product must not be returned to the refrigerator).



From a microbiological point of view the product should be used immediately, unless the method of reconstitution precludes the risk of microbial contamination. If not used immediately, in-use storage times and conditions are the responsibility of the user.



6.4 Special Precautions For Storage



Store at +2°C to +8°C. Do not freeze.



Store in the original container to protect from light.



May be removed from refrigeration and stored at temperatures not greater than 25 degrees C for up to six months or the pre-printed expiry date, whichever is shorter.



Once removed from refrigeration, record the expiry date on the product label.



6.5 Nature And Contents Of Container



All components are filled into glass containers conforming to EP requirements. The vials containing TISSEEL Powder are equipped with a magnetic spin propeller.



TISSEEL Kit is available in presentations of 0.5 ml, 1.0 ml, 2.0 ml, and 5.0 ml.



Each TISSEEL Kit contains the following:



1 vial containing TISSEEL Powder;



1 vial containing Thrombin Powder;



1 vial containing Aprotinin Solution;



1 vial containing Calcium Chloride Solution;



1 kit for reconstitution and application



Kit for Reconstitution and Application



Each kit contains one single-sterile set of devices for reconstitution under non-sterile conditions, and one double sterile set of devices for application under sterile conditions.



The set for reconstitution includes 2 disposable needles plus one blue-scaled disposable syringe and one black-scaled disposable syringe.



The set for application includes 2 disposable needles plus one blue-scaled disposable syringe and one black-scaled disposable syringe, one DUPLOJECT Two-Syringe Clip, 2 Joining Pieces and 4 Application Needles.



For details on reconstitution and application see the following section.



The sets of devices are sterile and non-pyrogenic in unopened and undamaged packages. Sterilised by exposure to ethylene oxide.



For single use only. Do not re-sterilise.



CE 0297



6.6 Special Precautions For Disposal And Other Handling



Preparation of Components



The rubber stoppers of all vials should be disinfected prior to reconstitution of the fibrin sealant components.



I. Preparation of TISSEEL Solution (First Component)



TISSEEL Powder is dissolved with the Aprotinin Solution to form TISSEEL Solution.



There are two ways of reconstituting TISSEEL Powder:



− Using the FIBRINOTHERM warming and stirring device.



− In a waterbath at a temperature of 37°C.



Reconstitution Using the FIBRINOTHERM device:



The FIBRINOTHERM device maintains a constant temperature of 37°C. It also shortens the dissolution time of the TISSEEL Powder due to the spin propeller contained in each TISSEEL Powder vial. The propeller is rotated by a magnet within the FIBRINOTHERM device.



Place the vials containing the TISSEEL Powder and Aprotinin Solution into the appropriate openings of the FIBRINOTHERM device and switch on using the red switch. When the FIBRINOTHERM device has reached a temperature of 37°C the red indication lamp goes out. Allow about 10 minutes for warming.



Transfer the Aprotinin Solution into the vial containing the TISSEEL Powder using one needle and the blue-scaled syringe included in the single-sterile kit for reconstitution.



Place the TISSEEL Powder vial into the largest opening of the FIBRINOTHERM device (if necessary, use adaptors). Turn on the stirrer using the green switch and stir the contents for 8 - 10 minutes.



Note: Keep the TISSEEL Solution at 37°C without stirring if it is not used immediately. To ensure homogeneity switch on the stirrer of the FIBRINOTHERM device shortly before drawing up the TISSEEL Solution into the blue-scaled syringe included in the double sterile kit for application.



Reconstitution Using Water-Bath:



Warm the vials containing the TISSEEL Powder and the Aprotinin Solution for about 10 minutes in a water-bath at a temperature of 37°C. (Avoid heating beyond 40°C.)



Transfer the Aprotinin Solution into the vial containing the TISSEEL Powder using one needle and the blue-scaled syringe included in the single-sterile kit for reconstitution.



Return the TISSEEL Powder vial to the water-bath at 37°C for one minute.



Swirl briefly but avoid excessive frothing. Then return the vial to the water-bath and check periodically for complete dissolution (see note).



Note: Always check that the TISSEEL Powder is fully dissolved: reconstitution is complete as soon as no undissolved particles are detectable when holding the vial against the light. If particles are present keep the vial at 37°C for a few more minutes and agitate the solution as before.



Keep the TISSEEL Solution at 37°C if it is not used immediately. To ensure homogeneity swirl briefly before drawing up the solution into the blue-scaled syringe included in the double sterile kit for application.



Withdraw the reconstituted TISSEEL Solution from the vial under sterile conditions.



II. Preparation of Thrombin Solution (Second Component)



Transfer the contents of the Calcium Chloride Solution vial into the Thrombin Powder vial. Use the second needle and the black-scaled syringe provided in the single-sterile kit for reconstitution.



Swirl briefly to dissolve the powder and then keep the Thrombin Solution at 37°C until used.



Prior to use draw up the Thrombin Solution from the vial using the second needle and the black-scaled syringe provided in the double-sterile kit for application.



Note: Syringes and needles used for the reconstitution of one component must not be re-used for the dilution of Aprotinin Solution or the reconstitution of the other component, as this would lead to solidification of the latter component in the vial or syringe.



7. Marketing Authorisation Holder



Baxter Healthcare Ltd.,



Caxton Way,



Thetford,



Norfolk,



UK,



IP24 3SE.



8. Marketing Authorisation Number(S)



PL 00116/0321



9. Date Of First Authorisation/Renewal Of The Authorisation



31st May 2000



10. Date Of Revision Of The Text



21st January 2005



TISSEEL, DUPLOCATH, DUPLOJECT, FIBRINOTHERM TISSOMAT, IMMUNO and HIQ-PCR are trademarks of Baxter AG, Vienna, Austria. BAXTER and HYLAND are trademarks of BAXTER International Inc.



[1] KIU = Kallidinogenase Inactivator Unit



[2] One International Unit (IU) of Thrombin is defined as the activity contained in 0.0853 mg of the First International Standard for Human Thrombin or the First International Standard for Alpha Thrombin Human.



[3] HIQ-PCR is a quality-assured PCR testing programme for genome equivalents of HIV-1 and -2, HBV, and HCV. HIQ-PCR stands for Hyland Immuno Quality-Assured Polymerase Chain Reaction.




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