Supportive treatment where standard surgical techniques are insufficient

- For improvement of hemostasis (see point 5.1)

- As a tissue glue to promote adhesion/sealing or as suture support:

            - in gastrointestinal anastomoses

            - in neurosurgery where contact with cerebro-spinal fluid or dura mater may occur

For mesh fixation in hernia repair, as an alternative or adjunct to sutures or staples.

TISSEEL Lyo is for topical (i.e., epilesional) use only, do not inject.

TISSEEL must not be applied intravascularly (see Section 4.4).

The use of TISSEEL Lyo is restricted to experienced surgeons who have been trained in the use of TISSEEL Lyo.

Posology

The amount of TISSEEL Lyo to be applied and the frequency of application should always be oriented towards the underlying clinical needs of the patient.

The dose to be applied is governed by variables including, but not limited to, the type of surgical intervention, the size of the area and the mode of intended application, and the number of applications.

To avoid the formation of excess granulation tissue and to ensure gradual absorption of the solidified fibrin sealant, as thin a layer as possible of TISSEEL Lyo should be applied.

If used for tissue adherence, it is recommended that the initial application cover the entire intended application area.

Application of the product must be individualized by the treating physician. In clinical trials, the individual dosages have typically ranged from 4 to 20 ml. For some procedures, larger volumes may be required.

The initial amount of the product to be applied at a chosen anatomic site or target surface area should be sufficient to entirely cover the intended application area. The application can be repeated, if necessary. However, avoid reapplication of TISSEEL Lyo to a pre-existing polymerized TISSEEL Lyo layer as TISSEEL Lyo will not adhere to a polymerized layer.

As a guideline for the gluing of surfaces, 1 pack of TISSEEL Lyo 2 ml (i.e. 1 ml Sealer Protein Solution plus 1 ml Thrombin Solution) will be sufficient for an area of at least 10 cm².

When TISSEEL Lyo is applied by spraying, the same quantity will be sufficient to coat considerably larger areas, depending on the specific indication and the individual case.

When TISSEEL Lyo is used for mesh fixation it may be applied as drops and/or by a spray technique depending on the preference of the surgeon. Usually the drops of TISSEEL are applied where surgeons routinely position staples and the layer of fibrin sealant achieved with spraying allows the entire mesh to be fixed in place without shrinking and folding.

The quantity of TISSEEL Lyo required for mesh fixation depends on the mesh size selected and the recommended amount is the same for different application techniques. For example, 2-4 ml of reconstituted TISSEEL Lyo applied as a thin layer is suitable to adequately fix a standard size mesh of approximately 10 x 15 cm.

When using the drop technique surgeons should apply TISSEEL Lyo at key anchor points for fixing the mesh (e.g. pubic tubercle in inguinal hernia repair) and at the margins of the mesh. Application by spray, either alone or in combination with drops, should cover the mesh uniformly with a thin layer.

In inguinal hernia repair the mesh covering vascular structures and nerves can be fixed with TISSEEL Lyo alone using drops and/or spray.

Paediatric population

Safety and efficacy of the product in paediatric patients have not been established.

Method and route of administration

For topical (i.e. epilesional) use only, do not inject.

Prepare the solutions as described at Section 6.6.

Prior to application, TISSEEL must be warmed to 33-37°C. Tisseel must not be exposed to temperatures above 37°C and must not be microwaved.

Separate, sequential application of the two components of TISSEEL must be avoided.

In order to ensure optimal safe use of TISSEEL Lyo by spray application the following recommendations should be followed:

In open wound surgery - a pressure regulator device that delivers a maximum pressure of no more than 2.0 bar (28.5 psi) should be used.

In minimally invasive/laparoscopic procedures – a pressure regulator device that delivers a maximum pressure of no more than 1.5 bar (22 psi) and uses carbon dioxide gas only should be used.

Prior to applying TISSEEL Lyo 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.

TISSEEL Lyo must be sprayed only onto application sites that are visible.

TISSEEL Lyo should only be reconstituted and administered according to the instructions and with the devices recommended for this product (see section 6.6).

For spray application, see sections 4.4 and 6.6 for specific recommendations on the required pressure and distance from tissue per surgical procedure and length of applicator tips.

Application beyond the intended area should be avoided.

If application is interrupted, clogging occurs immediately in the cannula. Replace the application cannula with a new one only immediately before application is resumed. If the aperture of the joining piece (Y connector) facing the cannula is clogged, use the spare joining piece provided in the package.

In surgical procedures that require the use of minimal volumes of fibrin sealant, it is recommended to expel and discard the first few drops of product immediately before application, to ensure use of adequate mixed product (see Section 4.4).

The sealer protein and thrombin solutions are denatured by alcohol, iodine, or heavy metal ions. If any of these substances have been used to clean the wound area, the area must be thoroughly rinsed before application of TISSEEL.

After TISSEEL has been applied allow at least 2 minutes to achieve sufficient polymerization. Depending on type of use, the sealed parts may have to be fixed or held in the desired position for this time.

Oxidised cellulose-containing preparations may reduce the efficacy of FS 500 and should not be used as carrier materials (see section 6.2).

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.

See Section 6.6 for more detailed instructions.

TISSEEL alone is not indicated for the treatment of severe or brisk arterial or venous bleeding which is not controlled by conventional surgical techniques.

For epilesional use only. Do not apply intravascularly. Soft tissue injection of TISSEEL Lyo carries the risk of an anaphylactoid reaction and / or local tissue damage.

Caution must be used when applying fibrin sealant using pressurized air or gas (See Section 4.2 and Section 4.8).

Life threatening thromboembolic complications may occur if the preparation is unintentionally applied intravascularly.

Intravascular application can lead to intravascular coagulation and may result in life-threatening thromboembolic events and might increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients.

TISSEEL must be applied with caution to minimize any risk of intravascular application, for example in coronary bypass surgery. Because of the risk of intravascular injection, the product also must not be injected into highly vascularized tissue, such as nasal mucosa.

In surgical applications that require the use of minimal volumes of fibrin sealant (e.g. pterygium surgery) the first few drops should be expelled and discarded before application to ensure adequate mixing of the sealer protein and thrombin solutions.

Use of the first few drops in these procedures could result in the product being ineffective.

In two retrospective, non-randomized studies in Coronary Artery Bypass Graft (CABG) surgery, patients that received fibrin sealant showed a statistically significant increased risk of mortality. While these studies could not provide a determination of a causal relationship the increased risk associated with the use of TISSEEL Lyo in these patients cannot be excluded. Therefore, additional care should be taken to avoid inadvertent intravascular administration of this product.

Injection of Sealer Protein Solution 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 Lyo and/or Thrombin Solution are only applied topically.

Caution must be used when applying fibrin sealant using pressurized gas. Any application of pressurized gas is associated with a potential risk of air or gas embolism, tissue rupture, or gas entrapment with compression, which may be life-threatening or fatal.

Apply TISSEEL Lyo as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and the wound healing process.

Life-threatening/fatal air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO₂ and therefore cannot be excluded with TISSEEL Lyo when sprayed in open wound surgery.

When applying TISSEEL Lyo using a spray device, be sure to use a pressure within the pressure range recommended by the spray device manufacturer (see table in section 6.6 for pressures and distances).

TISSEEL Lyo spray application should only be used if it is possible to accurately judge the spray distance as recommended by the manufacturer. Do not spray closer than the recommended distances.

When spraying TISSEEL Lyo, 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 (also see section 4.2).

TISSEEL Lyo must not be used with the EasySpray/Spray Set system in enclosed body areas.

Before the administration of TISSEEL Lyo, care is to be taken that parts of the body outside the designated application area are sufficiently protected/covered to prevent tissue adhesion at undesired sites.

If fibrin sealants are applied in confined spaces, e.g. the brain or the spinal cord, the risk of compressive complications should be taken into account.

As with any protein containing 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.

Intravascular application might increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients.

Manifestations of hypersensitivity reactions to TISSEEL observed include:

bradycardia, tachycardia, hypotension, flushing, bronchospasm, wheezing, dyspnoea, nausea, urticaria, angioedema, pruritus, erythema, paresthesia. Fatal anaphylactic reactions, including anaphylactic shock, have also been reported with TISSEEL see section 4.8).

At the first sign or symptom of a hypersensitivity reaction, TISSEEL application must be stopped and medical care initiated. Remaining product must be removed from the site of application.

Injection into the nasal mucosa must be avoided, as thromboembolic complications may occur in the area of the arteria ophthalmica.

Injecting TISSEEL Lyo into tissue carries the risk of local tissue damage.

TISSEEL Lyo contains synthetic aprotinin, a monomeric polypeptide known to be associated with anaphylactic reactions. Even in the case of strict local application of aprotinin there is a risk of anaphylactic reaction, particularly in the case of previous exposure. Aprotinin is included in TISSEEL for its antifibrinolytic properties. As with other aprotinin-containing products, the use of TISSEEL should be documented in the patient’s records, pointing out that TISSEEL contains aprotinin.

As synthetic aprotinin is structurally identical to bovine aprotinin the use of TISSEEL Lyo in patients with allergies to bovine proteins should be carefully evaluated.

In case of shock, standard medical treatment for shock should be implemented.

If fibrin sealants are applied in confined spaces, the risk of compressive complications should be taken into account.

Sealer Protein Solution and Thrombin Solution are made from human plasma. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections, and by inactivating and/or removing viruses.

Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses or other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped virus HAV.

The measures taken may be of limited value against small non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., hemolytic anemia).

It is strongly recommended that every time a patient receives a dose of TISSEEL Lyo, 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.

Oxidized cellulose-containing preparations should not be used with TISSEEL Lyo (See section 6.2 Incompatibilities).

Adequate data are not available to support the use of this product in application through a flexible endoscope for treatment of bleeding or in vascular surgery.

Safety and effectiveness of the product in pediatric patients has not been established as limited clinical study data are available.

No formal interaction studies have been performed. Similar to comparable products or thrombin solutions, the product 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 product.

There are no adequate data from the use of TISSEEL in pregnant or lactating women.

Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing TISSEEL.

No undesirable effects during pregnancy and lactation have been reported.

See section 4.4 for information on Parvovirus B19 infection.

The effects of TISSEEL Lyo on fertility have not been established.

Not relevant.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the application site, bradycardia, bronchospasm, chills, dyspnoea, flushing,  generalized urticaria, headache, hives, hypotension, lethargy, nausea, pruritus, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) may occur in rare cases in patients treated with fibrin sealants / hemostatics.

In isolated cases, these reactions have progressed to severe anaphylaxis. Such reactions may especially be seen, if the preparation is applied repeatedly, or administered to patients known to be hypersensitive to aprotinin (see section 4.4) or any other constituents of the product.

Even if a second treatment with TISSEEL Lyo was well tolerated, a subsequent administration of TISSEEL Lyo or systemic administration of aprotinin may result in severe anaphylactic reactions.

In the event of hypersensitivity reactions the administration has to be discontinued immediately.

Soft tissue injection of TISSEEL Lyo carries the risk of an anaphylactoid reaction and / or local tissue damage (see Section 4.4).

Reactions to antibodies against components of fibrin sealant / haemostatic products may occur rarely.

Inadvertent intravascular injection may result in thromboembolic events and disseminated intravascular coagulation, and there is also a risk of anaphylactic reaction (see section 4.4).

For safety with respect to transmissible agents, see section 4.4.

The following undesirable effects have been reported from clinical trials investigating the safety and efficacy of TISSEEL and from post-marketing experience with Baxter Fibrin Sealants. In these trials, TISSEEL was administered for adjunct haemostasis in cardiac, vascular total hip replacement and in liver and spleen surgeries. Other clinical trials included the sealing of lymphatic vessels in patients undergoing axillary lymph node dissection, sealing of colonic anastomosis and in durasealing in the posterior fossa. In these studies a total of 1146 patients were administered Baxter Fibrin sealant.

For the undesirable effects reported from post-marketing experience with Baxter Fibrin Sealants, the frequency cannot be estimated from the available data.

Very common (³ 1/10)

Common (³ 1/100 to <1/10)

Uncommon (³ 1/1,000 to <1/100)

Rare (³ 1/10,000 to <1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

* anaphylactic reactions and anaphylactic shock have included fatal outcomes.

** as a result of intravascular application into the superior petrosal sinus.

*** as with other fibrin sealants life-threatening/fatal air or gas embolism when using devices with pressurized air or gas occurred; 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.)

Class Reactions

Other adverse reactions associated with the fibrin sealant/hemostatic class include:

Air or gas embolism when using devices with pressurized air or gas; 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. Manifestations of hypersensitivity include application site irritation, chest discomfort, chills, headache, lethargy, restlessness, and vomiting.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the following national reporting system:

To report any side effect(s):

• Saudi Arabia:

• Other GCC States:

No case of overdose has been reported.

Pharmacotherapeutic group: local hemostatics, combinations, ATC code: B02BC30; tissue adhesives, ATC code: V03AK

The fibrin adhesion system imitates the last phase of physiological blood coagulation. Conversion of fibrinogen into 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 generated 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 anti-fibrinolytics. Aprotinin is present in TISSEEL Lyo as an antifibrinolytic.

Efficacy in haemostasis has been demonstrated in cardiopulmonary surgery, splenic surgery and neurosurgery.

Use as tissue glue to promote adhesion/sealing or as suture support: Efficacy has been demonstrated in surgeries including gastrointestinal anastomoses and neurosurgical procedures where contact with cerebro-spinal fluid or dura mater can occur.

Clinical studies demonstrating haemostasis, sealing, and tissue adhesion were conducted in at least 4,706 patients. These studies were performed in a multitude of surgical specialties, surgical procedures and applications techniques, including but not limited to haemostasis (n=1300), gastrointestinal anastomoses (n=1,114), neurosurgery (n=511).

21 open and comparative clinical studies have also been conducted in 2625 patients to demonstrate the use of TISSEEL in mesh fixation during inguinal, femoral and incisional hernia repair by various open and laparoscopic techniques. TISSEEL was at least as effective as staples, tacks or sutures in mesh fixation during the repair of inguinal or femoral hernia using all the currently favoured surgical techniques. TISSEEL was at least as effective in repair of incisional hernias when judged by recurrence rates. In addition, the evidence demonstrated that there were no differences in postoperative complications between mesh fixation methods. In several studies the level of postoperative pain was significantly lower in the TISSEEL group.

There is limited experience in children during cardiac surgery (age 4-134 months: n=14).

Efficacy has been demonstrated also in fully heparinized patients.

TISSEEL Lyo is intended for epilesional use only. As a consequence, intravascular pharmacokinetic studies were not performed in man. Fibrin sealants / haemostatics are metabolized in the same way as endogenous fibrin by fibrinolysis and phagocytosis.

No preclinical safety data are available for TISSEEL Lyo on acute toxicity, subacute and chronic toxicity, carcinogenicity or immune stimulation. None of the proteins contained in TISSEEL Lyo, 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.

6.1.1    Excipients of Sealer Protein Concentrate Lyophilized

Human albumin

L-histidine

Niacinamide

Sodium citrate dihydrate

Polysorbate 80 (Tween 80)

Water for Injections

6.1.2    Excipients of the Aprotinin Solution

Water for Injections

6.1.3    Excipients of Human Thrombin Lyophilized

Human Albumin

Sodium Chloride

6.1.4    Excipients of the Calcium Chloride Solution

Water for Injections

Sealer Protein and Thrombin Solutions can be denatured following contact with solutions containing alcohol, iodine or heavy metals. Tisseel must not be mixed with other medicinal products

Store at +2°C to +25°C (either in the refrigerator at +2°C to 8°C or at controlled room temperature (no exceeding +25°C).

Do not freeze.

Store in the original container to protect from light.

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

TISSEEL Lyo is available in presentations of 2 ml, 4 ml and 10 ml.

Each TISSEEL Lyo Kit contains the following:

-          1 vial containing Sealer Protein Concentrate Lyophilized;

-          1 vial containing Human Thrombin Lyophilized;

-          1 vial containing synthetic Aprotinin Solution;

-          1 vial containing Calcium Chloride Solution;

-          1 kit for reconstitution and application

6.5.1    Kit for Reconstitution and Application

Each kit contains one single-sterile set of devices for reconstitution under nonsterile 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

General

Before the administration of TISSEEL Lyo, care must be taken that parts of the body outside the desired application area are sufficiently covered to prevent tissue adhesion at undesired sites

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

Preparation and reconstitution

Prior to reconstitution of the fibrin sealant components, clean the rubber stoppers of all vials should be cleansed. Direct contact of disinfectant and product must be avoided (see Section 4.5).

I.       Preparation of Sealer Protein Solution (First Component)

Sealer Protein Concentrate Lyophilized is dissolved with the Aprotinin Solution to form Sealer Protein Solution.

Sealer Protein Concentrate Lyophilized is reconstituted using the FIBRINOTHERM warming and stirring device (recommended method). Alternatively, a sterile water bath at a temperature of 33 - 37°C can be used.

Reconstitution using the FIBRINOTHERM device:

The FIBRINOTHERM device maintains a constant temperature of 37°C. It also shortens the dissolution time of the Sealer Protein Concentrate Lyophilized by rotating the magnetic stirrer contained in each Sealer Protein Concentrate Lyophilized vial.

-       Place the vials containing Sealer Protein Concentrate Lyophilized and Aprotinin Solution into the appropriate openings of the FIBRINOTHERM device and preheat the vials for approximately 3 minutes.

-       Transfer the Aprotinin Solution into the vial containing the Sealer Protein Concentrate Lyophilized using one canula and the blue-scaled syringe provided in the single-sterile kit for reconstitution. Place Sealer Protein Concentrate Lyophilized vial into stirring well of the FIBRINOTHERM device (use an appropriate adaptor, if necessary) and stir until complete dissolution. Reconstitution is complete as soon as no particles are visible anymore when holding the vial against the light. If particles are present, keep on stirring the solution at 37°C for a few more minutes until complete dissolution. Turn off the magnetic stirrer when dissolution is complete.

Note: Excessive stirring might compromise product quality

-       Keep the Sealer Protein Solution at 37°C without stirring if it is not used immediately. To ensure homogeneity stir or swirl briefly before drawing up the Sealer Protein Solution into the blue-scaled syringe provided in the double sterile kit for application.

-       Withdraw the reconstituted Sealer Protein Solution from the vial under sterile conditions.

For further instructions please refer to the instructions for use of the FIBRINOTHERM device.

Reconstitution using a water bath:

-       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 - 37°C. (Heating beyond 37°C must be avoided)

-       Transfer the Aprotinin Solution into the vial containing the Sealer Protein Concentrate Lyophilized using one needle and the blue-scaled syringe provided in the single-sterile kit for reconstitution.

-       Return the Sealer Protein Concentrate Lyophilized vial to the water bath at 33 - 37°C for one minute.

-       Swirl briefly but avoid frothing. Then return the vial to the water bath and check periodically for complete dissolution. Reconstitution is complete as soon as no particles are visible when holding the vial against the light. If particles are present, keep the vial at a temperature of 33 - 37°C for a few more minutes and agitate until complete dissolution.

-       Keep the Sealer Protein Solution at 33 - 37°C after complete dissolution if it is not used immediately. To ensure homogeneity swirl briefly before drawing up the solution into the blue-scaled syringe provided in the double sterile kit for application.

-       Withdraw the reconstituted Sealer Protein Solution from the vial under sterile conditions.

Note: When using a water bath for reconstitution instead of the FIBRINOTHERM device special precautions have to be taken against submersing the vial, particularly the septum, to avoid possible contamination.

II.      Preparation of the Thrombin Solution – (Second Component)

The Human Thrombin Lyophilized is dissolved with the Calcium Chloride Solution to form the Thrombin Solution. Transfer the contents of the Calcium Chloride Solution vial into the Thrombin vial. Use the second needle and the black-scaled syringe provided in the single-sterile kit for reconstitution.

Swirl briefly to dissolve the lyophilized substance. To warm the Thrombin Solution either the FIBRINOTHERM device or a water bath can be used. Keep the Thrombin Solution at 33 - 37°C until use. 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 reused for reconstitution of the other component, as this would lead to premature solidification of that component in the vial or syringe.

III.    Use of reconstituted fibrin sealant components

Both fibrin sealant components must be used within 6 hours of reconstitution.

Administration

The Sealer Protein and the Thrombin Solutions should be clear or slightly opalescent. Do not use solutions which are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discoloration prior to administration.

Prior to administration, TISSEEL Lyo should be warmed to 33 - 37°C.

For application, place the two single-use syringes with the reconstituted Sealer Protein Solution and Thrombin Solution have to be clipped into the DUPLOJECT Two-Syringe Clip and connect this assembly to be connected to a joining piece and an application needle. All necessary devices are provided in the double-sterile kit for application.

The common plunger of the DUPLOJECT Two-Syringe Clip ensures that equal volumes are fed through the joining piece before being mixed in the application needle and ejected.

Operating instructions

-       Place the two syringes with the Sealer Protein Solution and with Thrombin Solution into the clip. Both syringes must be filled with equal volumes.

-       Connect the nozzles of both syringes to the joining piece ensuring that they are firmly fixed. Secure the joining piece by fastening the safety strap to the DUPLOJECT Two-Syringe Clip. Should the safety 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 needle onto the joining piece.

Do not expel the air remaining inside the joining piece or application needle until you start the actual application as the aperture of the needle may clog otherwise.

-       Apply the mixed Sealer Protein -Thrombin Solution on to the recipient surface or surfaces of the parts to be sealed.

For surgical procedures that require minimal volumes of fibrin sealant do not use the first few drops of TISSEEL Lyo (see Sections 4.2 and 4.4)

If application of the fibrin sealant components is interrupted, clogging occurs immediately in the needle. Replace the application needle with a new one only immediately before application is resumed. If the apertures of the joining piece are clogged, use the spare joining piece provided in the package.

Note: After blending of the sealant components, the fibrin sealant starts to set within seconds on account of the high Thrombin concentration (500 IU/ml).

Application is also possible with other accessories supplied by BAXTER that are particularly suited for, e.g., minimally invasive surgery, application to large or difficult-to-access areas. When using these application devices, strictly follow the Instructions for Use of the devices.

After two components have been applied, approximate the wound areas. Fix or hold the glued parts with continuous gentle pressure in the desired position to ensure that the setting fibrin sealant adheres firmly to the surrounding tissue. Allow at least 2 minutes to achieve sufficient polymerization.

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

Spray application

When applying TISSEEL Lyo using a spray device be sure to use a pressure and a distance from tissue within the ranges recommended by the manufacturer as follows:

When spraying the TISSEEL Lyo, 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 (see sections 4.2 and 4.4).

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.