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TISSEEL® KIT VH Baxter Fibrin Sealant
 
Description: Tisseel's action simulates key features of the physiological process of wound closure. A highly concentrated fibrinogen aprotinin solution, which among other ingredients contains Factor XIII, 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.

Tisseel-sealant is a tissue glue with sealing, hemostyptic and gluing properties, which does not interfere with but may enhance wound healing.

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 including orthopedic surgery, abdominal surgery, urology, vascular and cardiovascular surgery. The recently concluded cardiovascular safety study using the heat treated product has shown that Tisseel transmits neither hepatitis viruses nor HIV. Preclinical studies have shown that the vapor heated product is at least as effective as the heat treated product.

Use of the sealant 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 faster 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.

Indications And Clinical Uses :

Used to achieve hemostasis, to seal or glue tissue, and to support wound healing. Indications include: abdominal surgery, cardiovascular surgery, orthopedic surgery, thoracic surgery, urology.

Contra-Indications:

None known.:

WarningWarnings:

Warnings in Clinical States:

Since Tisseel is a plasma derivative, a risk of it transmitting viral hepatitis cannot be entirely ruled out. A recently concluded study with the heat treated product documented the safety of Tisseel with regard to a transmission of HIV-1 and hepatitis viruses. Today, Tisseel comes vapor heated, which further reduces any potential risk.

Neither of the 2 components, separately or combined, should be administered by the intravascular route, or thromboembolic complications will occur.

This product must not be used in animals.

Drug Interactions : Are not known. The sealant may be applied in fully heparinized patients (e.g. extracorporeal circulation).

Adverse Reactions: are not known

Dosage And Administration:

The required dose of Tisseel solution depends on the size of the surface to be sealed or coated or on the size of the defect to be packed (see Table I).

CPS:TABLE_C08000$$16_t1

Table I--Tisseel Kit VH

Required Dose of Tisseel Solution

Maximum size of the area to be sealed Required package sizes of Tisseel Kit VH

Application with spray head Other application methods

4 cm 2 Tisseel Kit VH 0.5

8 cm 2 Tisseel Kit VH 0.5 Tisseel Kit VH 1.0

16 cm 2 Tisseel Kit VH 1.0 Tisseel Kit VH 2.0

40 cm 2 Tisseel Kit VH 2.0 Tisseel Kit VH 5.0

100 cm 2Tisseel Kit VH 5.0

It is desirable for the Tisseel-sealant to be absorbed slowly during the wound healing process. For that reason, aprotinin solution is used for reconstitution of the freeze-dried Tisseel. The concentration of the aprotinin solution supplied with the kit may be varied to control the rate at which the sealant will be absorbed. If the aprotinin solution is diluted with sterile water for injection, the sealant will be absorbed faster. This may also be desirable if a recipient surface is known to have a low fibrinolytic activity of its own.

The setting rate of the sealant, on the other hand, depends on the concentration of the thrombin solution used. While the sealant may take up to 1 minute to set with a thrombin concentration of 4 IU/mL, this setting process will be complete within seconds if the higher thrombin concentration of 500 IU/mL is used. The higher thrombin concentration may be advantageous to achieve hemostasis, while the lower thrombin concentration is better apt to seal tissue because it allows time for approximation of the wound areas.

Various methods can be used to apply the two components of the sealant:

Simultaneous application: a) using Duploject and application needle; b) using Duploject and spray head; c) premixing.

Consecutive application.

Note: Simultaneous application by premixing requires a low thrombin concentration of 4 IU/mL while 500 IU/mL are recommended for the consecutive application method. Either concentration is suitable for applications using Duploject.

How to Prepare Tisseel Solution: Freeze-dried Tisseel is reconstituted in the Aprotinin Solution of 3 000 KIU/mL. To obtain lower concentrations, dilute the Solution with Sterile Water for Injection. For example, to obtain a concentration of 100 KIU/mL dilute 0.1 mL (0.2 mL if Tisseel Kit VH 5.0 is used) with 3 mL (5 mL) of Sterile Water for Injection using the blue-scaled syringe.

Reconstitution of Freeze-Dried Tisseel Using Fibrinotherm: For ease of handling, a combined heating and stirring device, Fibrinotherm, has been developed to meet the specific requirements of reconstituting freeze-dried Tisseel. Fibrinotherm is a thermoblock with a magnetic stirrer (the vials for freeze-dried Tisseel 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. Fibrinotherm has been designed to hold the various vial sizes of freeze-dried Tisseel and Aprotinin Solution.

Place vials containing freeze-dried Tisseel and Aprotinin Solution into the appropriate openings of Fibrinotherm and operate red flip switch. Wait until signal lamp goes out. Fibrinotherm has now reached 37°C. Preheat vials for 10 minutes.

Transfer Aprotinin Solution into vial containing freeze-dried Tisseel using blue-scaled syringe of corresponding size (or syringe that has been used for dilution of Aprotinin Solution).

Place vial into largest opening of Fibrinotherm (if necessary, use adaptors). Turn on stirrer with green flip switch and stir contents for 8 to 10 minutes.

Reconstitution of freeze-dried Tisseel is complete as soon as no undissolved particles are detectable in transparent light. Otherwise, replace into Fibrinotherm and agitate for another few minutes until the solution appears homogeneous.

Note: If not used immediately, keep Tisseel Solution at 37°C without stirring. To ensure homogeneity switch on stirrer of Fibrinotherm shortly before drawing up the solution.

Reconstitution of Freeze-Dried Tisseel Using a Water-Bath: Preheat the vial with freeze-dried Tisseel and the vial with the Aprotinin solution to about 37°C (but not beyond 40°C).

Transfer Aprotinin Solution into vial containing freeze-dried Tisseel using blue-scaled syringe of corresponding size (or syringe that has been used for dilution of Aprotinin Solution).

Allow vial to stand at 37°C for 1 minute.

Swirl briefly and vigorously with a circular motion (avoid excessive frothing) and replace vial into water-bath for another 10 to 15 minutes.

Reconstitution of freeze-dried Tisseel is complete as soon as no undissolved particles are detectable in transparent light. Otherwise, swirl again briefly and keep bottle at 37°C for a few more minutes.

Draw up reconstituted Tisseel 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 Tisseel Solution at 37°C. To ensure homogeneity, swirl with a circular motion (avoiding frothing) before drawing up the solution.

How to Prepare Thrombin Solution: Depending on the desired Thrombin concentration, either transfer the contents of the vial with Calcium Chloride Solution into the vial containing freeze-dried Thrombin 500 (quick solidification) or Thrombin 4 (slow solidification).

Use one of the sterile black-scaled syringes for preparing Thrombin Solution.

Swirl briefly. Keep Thrombin Solution at 37°C until used. Draw up an amount of Thrombin Solution equal to the amount of Tisseel Solution that will be used into a sterile black-scaled syringe using aseptic precautions.

Note: Do not use the syringes and needles previously used for reconstitution of freeze-dried Tisseel to prevent premature setting.

Simultaneous Application Using Duploject-System: The Duploject-System allows simultaneous application of the 2 components and ensures that they are quickly and thoroughly mixed, which is essential for the Sealant to gain the optimum strength. Either Thrombin concentration can be used.

Simultaneous Application Using Duploject and Application Needle: The sterile Duploject-System consists of a clip for 2 identical disposable syringes and a common plunger which ensures that equal volumes of the 2 components are fed over a common adjoining piece before mixed in the application needle and ejected.

Operating Instructions: Place syringes filled with Tisseel and Thrombin Solutions into the clip. Both syringes should be filled with equal amounts and should not contain any air bubbles.

Connect the nozzles of the 2 syringes with the joining piece. Ensure firm hold. Secure the joining piece by fastening the strap to the clip.

Fit application needle onto the joining piece. Do not remove remaining air from inside the joining piece or application needle. Otherwise the apertures of the needle may clog before application of the Sealant.

Apply Sealant onto the recipient surface or surfaces if 2 parts of tissue need to be glued together.

Note: Only the syringes contained in the Kit for reconstitution and application are designed to perfectly fit into the Duploject clip. Any other syringe may cause problems since exact and firm adaptation to the joining piece cannot be granted for. If the procedure of applying the 2 components with Duploject is interrupted, replace application needle by a new one when sealing is resumed (three spare needles come with the Kit). Only replace application needle immediately prior to resuming sealing. Otherwise, the apertures of the joining piece will clog, which requires it to be also replaced (one spare joining piece comes with the Kit).

Simultaneous Application Using Duploject and Spray Head: The spray head is particularly suitable for spraying of larger areas, e.g., to control oozing of parenchymateous organs.

Duploject is used for this method of application except that a spray head is used instead of the joining piece. Spray the 2 components simultaneously using sterile propellant gas and control the volume of the Solutions ejected with the Duploject plunger. Spray at a distance of 10 to 20 cm.

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

Simultaneous Application by Premixing: Mix equal volumes of the 2 components and immediately apply them to the recipient surface or surfaces. When the low Thrombin concentration of 4IU/ mL is used, approximately 1 minute is allowed for mixing the components, applying the Sealant, and approximating the wound areas. If desired, the Sealant can be mixed with spongiosa to pack bone defects.

Consecutive Application: Apply the 2 components in 2 layers. Apply Tisseel Solution to the recipient surface or surfaces first, then top with an equal amount of Thrombin Solution (500 IU/mL). Alternatively, when 2 parts are to be glued, apply one component to 1 surface, the other component to the opposite surface.

Note: To prevent the Sealant from adhering to gloves and instruments, wet these with saline before contact with Sealant.

Gluing of Tissue: After the 2 components have been applied, approximate the wound areas. Fix or hold the glued parts in the desired position for 3 or 5 minutes to ensure that the setting Sealant adheres firmly to the surrounding tissue. Solidified Sealant reaches its ultimate strength after about 2 hours (70% after about 10 minutes).

Note: In order to avoid excess formation of granulation tissue and slow absorption of the Sealant, only apply thin layers of the 2 components.

Availability And Storage:

The kit contains the following substances in 5 separate vials: 1. Sealer Protein Concentrate (Human)*, freeze dried, vapor treated. Reconstituted solution contains: total protein, 100-130 mg/mL; including fibrinogen, 70-110 mg/mL; Plasma fibronectin (cold insoluble globulin), 2-9 mg/mL; Factor XIII, 10-50 U/mL; plasminogen, 40-120 µg/mL. 2. Aprotinin solution, bovine 3 000 KIU/mL. 3. Thrombin 4 (bovine), freeze dried reconstituted contains: 4 IU/mL. 4. Thrombin 500 (bovine), freeze dried reconstituted contains: 500 IU/mL. 5. Calcium chloride solution, 40 mmol/L.

In addition each kit contains a sealant application set consisting of a Duploject applicator, disposable syringes, 2 joining pieces and 4 application needles.

In addition to the kit, a spray set is available.

Tisseel sealer protein concentrate is made from pooled fresh frozen human plasma. Donors of this plasma are tested at every donation for HB s-antigenemia, anti-HIV-1 or with elevated ALT levels are irrevocably excluded from the plasmapheresis program. In addition, Tisseel is subjected to a product-specific vapor heat treatment. Preclinical data show that this treatment produces a decrease in HIV-1 titer of 10

*Each vial contains a magnetic spin propeller to facilitate reconstitution when placed in the Fibrinotherm warming and stirring device.

Tisseel Kit 0.5 for 0.5 mL of reconstituted Tisseel solution and 0.5 mL Thrombin solution.

Tisseel Kit 1.0 for 1.0 mL of reconstituted Tisseel solution and 1.0 mL Thrombin solution.

Tisseel Kit 2.0 for 2.0 mL of reconstituted Tisseel solution and 2.0 mL Thrombin solution.

Tisseel Kit 5.0 for 5.0 mL of reconstituted Tisseel solution and 5.0 mL Thrombin solution.

Store between 2 and 8°C. Reconstituted solutions must be used within 4 hours.