In this leaflet:

1.    What TISSEEL is and what it is used for

2.    Before you use TISSEEL

3.    How to use TISSEEL

4.    Possible side effects

5.    How to store TISSEEL

6.    Further information

1.    WHAT TISSEEL IS AND WHAT IT IS USED FOR What TISSEEL is

The name of your medicine is TISSEEL Ready to use.

Throughout this leaflet TISSEEL Ready to use will be called TISSEEL.

TISSEEL is a two-component tissue sealant, and it contains two of the proteins that make blood clot. These proteins are called fibrinogen and thrombin. When these proteins mix during application, they form a clot where the surgeon applies them.

TISSEEL is prepared as two solutions (Sealer Protein Solution and Thrombin Solution), which mix when applied. What TISSEEL is used for

TISSEEL is a fibrin or tissue sealant. During surgery, tissues may bleed and it may not be possible for the surgeon to control this bleeding using stitches, or by applying pressure. TISSEEL is applied to the surface of tissues, either to control bleeding, or to stop (or prevent) leaks of other types of fluid, by creating a watertight seal.

TISSEEL can be used even if your blood does not clot properly, e.g. when you are being treated with heparin against thrombosis. It is also used as a tissue glue to achieve adhesion/sealing or as suture support in surgery. In addition, TISSEEL is used to fix mesh during hernia repair surgery.

The clot produced by TISSEEL is very similar to a natural blood clot and this means that it will dissolve naturally and leave no residue. However, aprotinin is added to increase the longevity of the clot and to prevent its premature dissolution.

2.    BEFORE YOU USE TISSEEL

Do not use TISSEEL in the following situations:

•    TISSEEL must not be used for massive or brisk bleeding.

•    TISSEEL MUST NOT be injected into blood vessels (veins or arteries), or into tissues. As TISSEEL forms a clot where it is applied, injecting TISSEEL may cause serious reactions. TISSEEL should only be applied to the surface of tissues as a thin layer where it is needed. If you are going to have a coronary bypass surgery, special care needs to be taken to avoid injecting TISSEEL into blood vessels

•    If you are allergic (hypersensitive) to synthetic proteins or any of the other ingredients, TISSEEL must not be used.

TISSEEL contains a synthetic protein, called aprotinin. Even when this protein is applied in small areas, there is a risk of a reaction known as anaphylaxis, or a severe allergic (hypersensitive) reaction.

Take special care with TISSEEL

•    Life-threatening/fatal air or gas embolism (air getting into the blood circulation which can be serious or life-threatening) has occurred very rarely with the use of spray devices employing pressure regulators to administer fibrin sealants. This 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 when sprayed in open wound surgery.

•    Spray devices and the accessory tip provide instructions for use with recommendations for pressure ranges and to the spraying distance from the tissue surface.

•    TISSEEL should be administered strictly according to the instructions and only with devices recommended for this product.

•    When spraying TISSEEL, changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored for possible occurrence of gas embolism.

•    If you have ever received TISSEEL or aprotinin before, your body may have become sensitive to it. It is possible you may be allergic to this material, even if there was no reaction to the first application. If you think you have received either product in a previous operation, you have to inform your doctor about this.

•    If the surgeon or operating team sees any sign of an allergic reaction during the application of TISSEEL, they will stop using TISSEEL immediately and will take the adequate measures.

Using other medicines

There are no known interactions between TISSEEL and other medicinal products.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Taking TISSEEL with food and drink

Please ask your doctor. The doctor will decide if you are allowed to eat and drink before the application of TISSEEL. Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. Please inform your doctor before using TISSEEL if you are or could be pregnant or if you are breast-feeding. Your doctor will decide if you can use TISSEEL during pregnancy or breast-feeding.

Driving and using machines

TISSEEL will not affect your ability to drive or operate other types of machines.

Important information about the potential risk of infection from donor human plasma

When medicines are made from human blood or plasma, certain steps are taken to prevent infections being passed on to patients. Blood and plasma donors are carefully selected to make sure that those at risk of carrying infections are excluded.

In addition, each donation and plasma pool is tested for signs of viruses or infections. Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.

Recommended pressure, distance and devices for spray application of TISSEEL
Surgery	Spray set to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recommended spray pressure
Open wound	Tisseel / Artiss Spray Set	n.a.	EasySpray	10 - 15 cm	1.5 - 2.0 bar (21.5 - 28.5 psi)
	Tisseel / Artiss Spray Set 10 pack	n.a.	EasySpray
Laparoscopic/ minimally invasive procedures	n.a.	Duplospray MIS Applicator 20 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11	2 - 5 cm	1.2 - 1.5 bar (18 - 22 psi)
		Duplospray MIS Applicator 30 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Duplospray MIS Applicator 40 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Replaceable tip	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11

When spraying the 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 (see section 2).

If you take more TISSEEL than you should

TISSEEL is only applied during a surgical operation. It is applied by the surgeon and the amount of TISSEEL is determined by the surgeon.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.    POSSIBLE SIDE EFFECTS

Like all medicines, TISSEEL can cause side effects, although not everybody gets them.

•    There is a slight possibility that you might react allergically to one of the components of TISSEEL. This is more likely if you have been treated with TISSEEL or aprotinin during a previous operation. Allergic reactions can be serious, and it is very important that you discuss this possibility in detail with your doctor.

•    In very rare cases, allergic reactions of the anaphylactic/anaphylactoid type may occur. Early symptoms of allergic reactions can be: flushing, a fall in blood pressure, increased or decreased pulse rate, nausea (feeling sick), hives, itching, difficulty breathing.

•    The surgical team treating you will be aware of the risk of this type of reaction - if they see any symptoms, the application of TISSEEL will be stopped immediately. Severe symptoms may require emergency treatment.

•    If TISSEEL is injected into soft tissues, it can cause local tissue damage.

•    If TISSEEL is injected into blood vessels (veins or arteries), it can cause clots to form (thrombosis).

•    As TISSEEL is made from plasma from blood donations, the risk of infection cannot be totally excluded, but the manufacturer undertakes numerous measures to reduce the risk (see section 2).

•    There are also individual reports on occurrence of bleeding, blockage of bowel passageway, impaired healing, swellings caused by accumulation of fluid in body tissue, fever, and accumulation of lymph and other clear body fluids near the surgical site.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5.    HOW TO STORE TISSEEL

•    Keep out of the reach and sight of children.

•    Do not use TISSEEL after the expiry date given on the label.

•    Store at <-18°C (in a freezer). The cold storage chain must not be interrupted until use.

•    Keep TISSEEL in the original package, to protect from light.

•    After thawing, the solution must not be refrozen or refrigerated!

6.    FURTHER INFORMATION What TISSEEL contains

TISSEEL contains two components:

Component 1 = Sealer Protein Solution:

The active substances contained in 1ml of the Sealer Protein solution are:

Human Fibrinogen, 72 - 110 mg/ml; Aprotinin (synthetic), 3000 KIU/ml.

The excipients are Human Albumin, L-Histidine, Niacinamide, Polysorbate 80, Sodium Citrate Dihydrate and Water for Injections.

Component 2 = Thrombin Solution:

The active substances contained in 1 ml of the Thrombin Solution are:

Human Thrombin, 500 IU/ml; Calcium Chloride, 40 pmol/ml.

The excipients are Human Albumin, Sodium Chloride and Water for Injections.

What TISSEEL looks like and the contents of the pack

Both components of TISSEEL Sealer Protein Solution and Thrombin Solution are filled in single-use doublechamber syringes made of polypropylene. Both components are colorless or pale yellow.

Each pack of TISSEEL contains

•    One pre-filled double-chamber syringe with Sealer Protein Solution (with aprotinin), deep-frozen, in one chamber; and Thrombin Solution (with calcium chloride), deep frozen, in the other chamber.

•    One set of sterile accessory devices (Duo Set: 1 syringe plunger, 2 joining pieces and 4 application cannulas). TISSEEL is available in the following pack sizes:

• TISSEEL 2 ml (containing 1 ml of Sealer Protein Solution and 1 ml of Thrombin Solution)

• TISSEEL 4 ml (containing 2 ml of Sealer Protein Solution and 2 ml of Thrombin Solution)

•    TISSEEL 10 ml (containing 5 ml of Sealer Protein Solution and 5 ml of Thrombin Solution)

TISSEEL is available in pack sizes of 2 ml, 4 ml and 10 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder:

Baxter Healthcare Caxton Way Thetford Norfolk UK

IP24 3SE

Manufacturer

Baxter AG IndustriestraBe 67 A-1221 Vienna Austria

This leaflet was last approved in: 03/2013

The following information is intended for medical or healthcare professionals only:

Instructions for use and handling and disposal General

Before administering TISSEEL, take care that parts of the body outside the intended application area are adequately covered, so that the medicine does not adhere to tissue at undesired sites.

For surgical procedures that require minimal volumes of fibrin sealant, do not use the first few drops of Tisseel Ready to use. In order to ensure complete blending of the sealer protein component and the thrombin component, express the first few drops of the product from the application cannula immediately before use and dispose of them. To prevent TISSEEL from adhering to gloves and instruments, wet these with saline before contact.

Some solutions that contain alcohol, iodine or certain types of metals (these are normally found in disinfectants or antiseptics) may reduce the ability of TISSEEL to work normally. These substances should be removed, as far as possible, before TISSEEL is applied.

It is strongly recommended that every time you receive a dose of TISSEEL, the name and batch number of the product are recorded. This maintains a record of the batches used.

Handling and Preparation

The pre-filled double-chamber syringe is packed and hermetically sealed in two sterilized plastic bags under aseptic conditions. The inner bag and its contents are sterile unless the integrity of the outside package is compromised.

It is recommended to thaw and warm the two sealant components using a sterile water bath at a temperature of 33 - 37°C. The water bath must not exceed a temperature of 37°C. (Check that the temperature is within range by monitoring the water temperature with a thermometer and changing the water as necessary. When using a sterile water bath for thawing and warming, the pre-filled double-chamber syringe should be removed from the aluminium plastic bags.)

The protective syringe cap should not be removed until thawing is complete and application tip is ready to be attached. Do not use TISSEEL unless it is completely thawed and warmed (liquid consistency).

Thaw pre-filled syringes in one of the three following options:

The thawing and warming times when using a sterile water bath are indicated in table 1 below:

Table 1: Thawing and Warming Times with Sterile Water Bath at 33°C to a maximum of 37°C

Pack Size	Thawing and Warming Times (product removed from plastic bags)
2 ml	5 minutes
4 ml	5 minutes
10 ml	12 minutes

Alternatively, the sealant components may be thawed and warmed in an incubator in between 33°C and 37°C. The thawing and warming times in the incubator are indicated in Table 2 below. The times refer to product in the aluminium plastic bags.

Table 2: Thawing and Warming Times in Incubator at 33°C to a maximum of 37°C

Pack Size	Thawing and Warming Times in Incubator (product in plastic bags)
2 ml	40 minutes
4 ml	85 minutes
10 ml	105 minutes

A third alternative is to thaw the product at room temperature. Times given in Table 3 are minimum times for thawing at room temperature. The maximum time the product can be kept (in both plastic bags) at room temperature is 72 hours.

When thawing at room temperature, the product must be additionally warmed to 33°C - 37°C in an incubator shortly before use in order to allow for optimum blending of the two solutions. Respective thawing times in the incubator are also given in Table 3.

Table 3. Thawing and Warming times at Room Temperature (=RT) followed by an additional warming, prior to use, in incubator at 33°C to a maximum of 37°C

Pack Size	Thawing Times at Room Temperature (product in plastic bags)	Warming Times at 33 - 37°C in Incubator after thawing at RT (product in plastic bags)
2 ml	60 minutes + 15 minutes
4 ml	110 minutes + 25 minutes
10 ml	160 minutes + 35 minutes

Note: Do not thaw by holding product in your hands.

Do not microwave.

After thawing do not refrigerate or refreeze.

To facilitate blending of the two solutions and allow for optimum solidification of the blend, the two sealant components must be warmed to 33 - 37°C. (The temperature of 37°C must, however, not be exceeded!)

The pre-filled double-chamber syringe should not be removed from the plastic bags until shortly before use and the protective caps of the syringes should not be taken off until shortly before application.

Administration

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

Thawed, unopened pouches may be stored for up to 72 hours at controlled room temperature (not exceeding +25°C). Prior to administration, TISSEEL should be warmed to 33 - 37°C.

For application of TISSEEL use the pre-filled double-chamber syringe with the Duo Set accessory devices provided with the product.

Operating Instructions

For application, connect the double-chamber syringe with the Sealer Protein Solution and the Thrombin Solution to a joining piece and an application needle as provided in the accompanying set of devices. The common plunger of the double-chamber syringe ensures that the equal volumes are fed through the joining piece before being mixed in the application needle and ejected.

•    Connect the double-chamber syringe nozzles to the joining piece and secure it by fastening the tether strap to the double-chamber syringe. If the pull strap tears, use the spare joining piece. If none is available, further use is still possible but check that the connection is tight, to prevent any risk of leaking.

•    Fit an application cannula onto the joining piece.

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

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

•    When Tisseel 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 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.

•    If application of the fibrin sealant components is interrupted, clogging occurs immediately in the needle. Only 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 mixing of the sealant components, the fibrin sealant starts to set within seconds, because 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., endoscopic use, 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 the two components have been applied, position the wound areas. Fix or hold the glued parts with continuous gentle pressure in the desired position for about 3 - 5 minutes to ensure that the setting fibrin sealant adheres firmly to the surrounding tissue.

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

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

Recommended pressure, distance and devices for spray application of TISSEEL
Surgery	Spray set to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recommended spray pressure
Open wound	Tisseel / Artiss Spray Set	n.a.	EasySpray	10 - 15 cm	1.5 - 2.0 bar (21.5 - 28.5 psi)
	Tisseel / Artiss Spray Set 10 pack	n.a.	EasySpray
Laparoscopic/ minimally invasive procedures	n.a.	Duplospray MIS Applicator 20 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11	2 - 5 cm	1.2 - 1.5 bar (18 - 22 psi)
		Duplospray MIS Applicator 30 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Duplospray MIS Applicator 40 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Replaceable tip	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11

When spraying the 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 (see section 2).

Baxter

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

TISSEEL Ready to use Solutions for Sealant

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Component 1:

Sealer Protein Solution

Human Fibrinogen (Clottable Protein)    91 mg⁽¹⁾/ml

Aprotinin (synthetic)    3000 KIU⁽²⁾/ml

Component 2:

Thrombin Solution

Human Thrombin    500 I U⁽³⁾/ml

Calcium Chloride    40 pmol/ml

¹    Contained in a total protein concentration of 110.5 mg/ml

²    1 EPU (European Pharmacopoeia Unit) corresponds to 1800 KIU (Kallidinogenase Inactivator Unit)

³    Thrombin activity is calculated using the current WHO International Standard for Thrombin.

For excipients, see section 6.1.

1 prefilled double chamber syringe which contains Sealer Protein Solution (with synthetic Aprotinin), deep frozen 1 ml, 2 ml, or 5 ml, in one chamber and Thrombin Solution (with Calcium Chloride), deep frozen 1 ml, 2 ml, or 5 ml, in the other chamber results in 2 ml, 4 ml, or 10 ml total volume of product ready for use.

3    PHARMACEUTICAL FORM

Solutions for Sealant

Colourless to pale yellow and clear to slightly turbid solutions.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Supportive treatment where standard surgical techniques are insufficient

-    for improvement of hemostasis (see section 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.

4.2    Posology and method of administration

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

Posology

The amount of TISSEEL Ready to use to be applied and the frequency of application should always be oriented towards the underlying clinical needs for 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, only a thin layer of TISSEEL Ready to use should be applied.

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.

As a guideline for the gluing of surfaces, 1 pack of TlSSEEL Ready to use 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 Ready to use 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 Ready to use 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 Ready to use 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 Ready to use 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 Ready to use 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 Ready to use alone using drops and/or spray.

Method and route of administration

For epilesional use.

In order to ensure optimal safe use of TISSEEL 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 the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

TISSEEL 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.

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 (see Section 4.4).

4.3    Contraindications

TISSEEL Ready to use must not be applied intravascularly.

Hypersensitivity to the active substances or to any of the excipients (see also section 4.4. Warnings).

TISSEEL Ready to use alone is not indicated for the treatment of active or spurting arterial or venous bleeding which is not controlled by conventional surgical techniques.

4.4    Special warnings and precautions for use

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

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 Ready to use in these patients cannot be excluded. Therefore, additional care should be taken to avoid inadvertent intravascular administration of this product.

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

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.

Apply TISSEEL 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 when sprayed in open wound surgery.

When applying TISSEEL 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 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, changes in .blood pressure, . pulse, oxygen . saturation and end tidal CO_? should be monitored because of the possibility of occurrence of air or gas embolism (also see section 4.2).

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.

TISSEEL Ready to use contains synthetic aprotinin. Even in the case of strict local application there is a risk of anaphylactic reaction, linked to the presence of 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.

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

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

Sealer Protein Solution and Thrombin Solution are made from human plasma. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation / removal of 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. haemolytic anemia).

It is strongly recommended that every time a patient receives a dose of TISSEEL Ready to use, the name and batch number of the product are recorded in order to maintain a record of the batches used.

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.

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, 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.

4.6    Pregnancy and lactation

The safety of fibrin sealants for use in human pregnancy or breastfeeding has not been established in controlled clinical trials. Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or fetus, the course of gestation and peri-and postnatal development.

Therefore, the product should be administered to pregnant and lactating women only if clearly needed.

4.7    Effects on ability to drive and use machines Not relevant.

4.8    Undesirable effects

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 / haemostatics.

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 Ready to use was well tolerated, a subsequent administration of TISSEEL 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 Ready to use 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 could lead to 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 undesirable effects reported in the listing hereafter are based on post-market experience for this type of product. Their frequency has been evaluated by using the following criteria: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), and very rare (<1/10,000).

The undesirable effects listed below reflect the type of undesirable effects that have been reported with TISSEEL Ready to use.

Their incidence rate is <1/10,000, i.e. very rare.

Cardiac disorders

•    Bradycardia, Tachycardia Gastrointestinal disorders

•    Nausea

General disorders and administration site disorders

•    Hypersensitivity reactions Immune system disorders

•    Anaphylactic reactions, Allergic reactions, Anaphylactic shock, Urticaria Injury, poisoning and procedural complications

•    Anaphylactoid reactions Investigations

•    Drop in blood pressure

Respiratory, thoracic and mediastenal disorders

•    Dyspnoea

Skin and subcutaneous tissue disorders

•    Pruritus Vascular disorders

•    Flush, (severe) Hypotension, Thromboembolic complication

4.9    Overdose

No case of overdose has been reported.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: local hemostatics, ATC code: B02BC; tissue adhesives, ATC code: V03A K 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 the concerted action of thrombin and calcium ions, stabilizes the clot by the cross-linking of fibrin fibres.

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 Ready to use as an antifibrinolytic to prevent premature degradation of the clot.

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).

Fibrin Sealant VH S/D (frozen presentation) was evaluated in a prospective, parallel design, randomized (1:1), double-blind, multicenter clinical study against a previous single virus inactivated formulation of the product, Fibrin Sealant VH (lyophilized presentation), in 317 subjects undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) and median sternotomy. Patients were treated with Fibrin Sealant VH S/D 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, Fibrin Sealant VH S/D was non-inferior to the earlier formulation of the product using a one-sided 97.5% confidence interval on the difference in the proportion of subjects successfully treated.

Hemostasis within 5 minutes and maintained until surgical closure
	FIBRIN SEALANT VH S/D	FIBRIN SEALANT VH
Intent to Treat Analysis	127/144 (88.2%)	129/144 (89.6%)
Per Protocol Analysis	108/123 (87.8%)	122/135 (90.4%)

No difference to control groups not receiving Fibrin Sealant VH S/D was observed in an exploratory study in hip joint replacement for postoperative blood loss and in a study in axillary lymph node dissection for duration of axillary drainage.

5.2 Pharmacokinetic properties

Intravascular administration is contraindicated. As a consequence, intravascular pharmacokinetic studies were not performed in man.

Fibrin sealants/hemostatics are metabolized in the same way as endogenous fibrin by fibrinolysis and phagocytosis.

5.3 Preclinical safety data

No preclinical safety data are available for Fibrin Sealant VH S/D on subacute and chronic toxicity, carcinogenicity, reproductive and developmental toxicity or immune stimulation.

Single-dose toxicity studies in rats and rabbits indicated no acute toxicity of Fibrin Sealant VH S/D (frozen presentation). There was no evidence of mutagenicity in appropriate in vitro tests.

Fibrin Sealant VH S/D (frozen presentation) was well tolerated in wound healing models in rats and rabbits.

The Sealer Protein Solutions of Fibrin Sealant VH S/D (frozen and lyophilized presentations) were also well tolerated by in vitro human fibroblast cultures demonstrating cellular compatibility and non-cytotoxicity.

Based on a detailed literature review, toxicity of the residual solvent/detergent reagents (see 6.1) on Fibrin Sealant VH S/D can be essentially excluded.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Component 1: Sealer Protein Solution

Human Albumin

L-Histidine

Niacinamide

Polysorbate 80 (Tween 80)

Sodium Citrate Dihydrate Water for Injections Component 2: Thrombin Solution Human Albumin Sodium Chloride Water for Injections

6.2    Incompatibilities

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.

6.3    Shelf life

TISSEEL Ready to use has a shelf life of two years. The expiry date is stated on the package.

Shelf life for thawed product see section 6.6.

6.4    Special precautions for storage

Keep out of the reach and sight of children.

Store in a freezer (at <-18°C). The cold storage chain must not be interrupted until use.

Keep TISSEEL Ready to use in the outer carton to protect from light.

Use the thawed solutions within 72 hours. Do not refreeze or refrigerate after thawing.

6.5    Nature and contents of container

Both Sealer Protein Solution and Thrombin Solution are contained in a single-use double-chamber syringe made of polypropylene.

Each pack of TISSEEL Ready to use contains:

•    One single-use double-chamber syringe with Sealer Protein Solution 1 ml, 2 ml, or 5 ml, deep-frozen, in one chamber; and Thrombin Solution 1 ml, 2 ml, or 5 ml, deep frozen, in the other chamber.

1)    One chamber contains: Component 1 - Sealer Protein Solution

Active substances: Human Fibrinogen (Clottable Protein) 72 - 110 mg/ml, Aprotinin (synthetic) 3000 KlU/ml

2)    One chamber contains: Component 2 - Thrombin Solution

Active substances: Human Thrombin 500 lU/ml, Calcium Chloride 40 pmol/ml

•    One set of application devices (DUO - Set: 2 joining pieces, 4 application needles (blunt), 1 Double syringe plunger)

TISSEEL Ready to use is available in the following pack sizes:

•    TISSEEL Ready to use 2 ml

(containing 1 ml of Sealer Protein Solution and 1 ml of Thrombin Solution)

•    TISSEEL Ready to use 4 ml

(containing 2 ml of Sealer Protein Solution and 2 ml of Thrombin Solution)

•    TISSEEL Ready to use 10 ml

(containing 5 ml of Sealer Protein Solution and 5 ml of Thrombin Solution)

Not all pack sizes may be marketed.

Other accessories for application of the product can be obtained from BAXTER.

6.6    Special precautions for disposal General

Before administration of TISSEEL Ready to use care has to 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 Ready to use from adhering to gloves and instruments, wet these with sodium chloride solution before contact.

Handling and Preparation

Both the Sealer Protein Solution and the Thrombin Solution are contained in a single-use double-chamber syringe. The nozzles of the pre-filled double-chamber syringe are closed by one tip cap and each barrel of the syringe is closed by a silicone rubber stopper. The entire assembly is packed and hermetically sealed in two sterilized aluminum-plastic-compound bags under aseptic conditions. The inner bag and its contents are sterile unless the integrity of the outside package is compromised.

It is recommended to thaw and warm the two sealant components using a sterile water bath at a temperature of 33 - 37°C. The water bath must not exceed a temperature of 37°C. (In order to control the specified temperature range, the water temperature should be monitored using a thermometer and the water should be changed as necessary. When using a sterile water bath for thawing and warming, the pre-filled double chamber syringe assembly should be removed from the aluminum-plastic bags.)

The protective syringe cap should not be removed until thawing is complete and application tip is ready to be attached. Do not use TISSEEL Ready to use unless it is completely thawed and warmed.

Thaw pre-filled syringes in one of the three following options:

The thawing and warming times when using a sterile water bath are indicated in Table 1 below. Table 1: Thawing and Warming Times with Sterile Water Bath at 33°C to a maximum of 37°C

Pack Size	Thawing and Warming Times (product removed from aluminum-plastic bags)
2 ml	5 minutes
4 ml	5 minutes
10 ml	12 minutes

Alternatively, the sealant components may be thawed and warmed in an incubator between 33°C and 37°C. The thawing and warming times in the incubator are indicated in Table 2 below. The times refer to product in the aluminum-plastic bags.

Table 2: Thawing and Warming Times in Incubator at 33°C to a maximum of 37°C

Pack Size	Thawing and Warming Times in Incubator (product in aluminum-plastic bags)
2 ml	40 minutes
4 ml	85 minutes
10 ml	105 minutes

A third alternative is to thaw the product at room temperature. Times given in Table 3 are minimum times for thawing at room temperature. The maximum time the product can be kept (in both aluminum-plastic bags) at room temperature is 72 hours.

When thawing at room temperature, the product must be additionally warmed to 33°C - 37°C in an incubator just before use. Respective thawing times in the incubator are also given in Table 3.

Table 3. Thawing and warming times at Room Temperature (=RT) followed by an additional warming, prior to use, in Incubator at 33°C to a maximum of 37°C

Pack Size	Thawing Times at Room Temperature (product in aluminum-plastic bags)	Warming Times at 33 - 37°C in Incubator after thawing at RT (product in aluminum-plastic bags)
2 ml	60 minutes + 15 minutes
4 ml	110 minutes + 25 minutes
10 ml	160 minutes + 35 minutes

Note: Do not thaw by holding product in your hands.

Do not microwave.

After thawing do not refrigerate or refreeze.

To facilitate optimal blending of the two solutions, the two sealant components must be warmed to 33 - 37°C immediately before use. (The temperature of 37°C must, however, not be exceeded!)

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

The thawed Sealer Protein Solution should be a slightly viscous liquid. If the solution has the consistency of a solidified gel, it must be assumed to have become denatured (e.g., due to an interruption of the cold storage chain or by overheating during warming). In this case, the TISSEEL Ready to use must not be used.

Thawed, unopened pouches may be stored for up to 72 hours at controlled room temperature (not exceeding +25°C) after removal from the freezer. If not used within 72 hours after thawing, TISSEEL Ready to use has to be discarded. Once thawed, TISSEEL Ready to use must not be refrozen or refrigerated (the sealer protein component forms a gel at refrigerator temperature).

For further preparation instructions please refer to the responsible nurse or medical doctor.

ADMINISTRATION

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 needle as provided in the accompanying set of devices. The common plunger of the double-chamber syringe ensures that equal volumes are fed through the joining piece before being mixed in the application needle and ejected.

-    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. If the pull strap tears, 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 actual application as the aperture of the needle may clog otherwise.

-    Apply the mixed Sealer Protein-Thrombin Solution onto 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 Ready to use (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. endoscopic use, 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 the two components have been applied, approximate the wound areas. Fix or hold the glued parts with continuous gentle pressure in the desired position for about 3 - 5 minutes to ensure that the setting fibrin sealant adheres firmly to the surrounding tissue.

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

Spray application

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

Recommended pressure, distance and devices for spray application of TISSEEL
Surgery	Spray set to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recommended spray pressure
Open wound	Tisseel / Artiss Spray Set	n.a.	EasySpray	10 - 15 cm	1.5 - 2.0 bar (21.5 - 28.5 psi)
	Tisseel / Artiss Spray Set 10 pack	n.a.	EasySpray
Laparoscopic/ minimally invasive procedures	n.a.	Duplospray MIS Applicator 20 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11	2 - 5 cm	1.2 - 1.5 bar (18 - 22 psi)
		Duplospray MIS Applicator 30 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Duplospray MIS Applicator 40 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Replaceable tip	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11

When spraying the 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 (see sections 4.2 and 4.4).

Disposal

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

7    MARKETING AUTHORISATION HOLDER

Baxter Healthcare Limited, Caxton Way, Thetford, Norfolk, IP24 3SE, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 00116/0627

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/10/2008

10    DATE OF REVISION OF THE TEXT

15 March 2013

0722762_GB_V1.indd 8 03.04.13 09:59

1

   HOW TO USE TISSEEL

•    TISSEEL is only applied during a surgical operation. The use of TISSEEL is restricted to experienced surgeons who have been trained in the use of TISSEEL.

2

•    The amount of TISSEEL that will be used depends on a number of factors, including the type of surgery, the surface area of tissue to be treated during your operation and the way TISSEEL is applied. The surgeon will decide how much is appropriate, and will apply just enough to form a thin, even layer over the tissue. If this does not seem to be enough, a second layer can be applied.

3

•    During your operation, the surgeon will apply TISSEEL onto the relevant tissue surface, using the special application device provided. This device ensures that equal amounts of both components are applied at the same time - which is important for the optimal effect of TISSEEL.

4

•    For hernia repair surgery the surgeon will apply Tisseel using spray or drops to fix the mesh in place.

5

•    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).

6

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