TISSEEL Tissue Adhesive Solution

Introduction

Package Leaflet: Information for the User

TISSEEL Tissue Adhesive Solutions

Human fibrinogen, human thrombin, synthetic aprotinin, calcium chloride dihydrate

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you experience any side effects, talk to your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the Package Leaflet

1. What is TISSEEL and what is it used for
2. What you need to know before you start using TISSEEL
3. How to use TISSEEL
4. Possible side effects
5. Storage of TISSEEL
6. Contents of the pack and further information

1. What is TISSEEL and what is it used for

What isTISSEEL

TISSEEL is a two-component tissue adhesive consisting of two solutions, the sealant protein solution and the thrombin solution. TISSEEL contains fibrinogen and thrombin. These are two important blood proteins for blood coagulation. When these proteins are mixed during application, they form a clot at the site of application.

The clot produced by TISSEEL is very similar to the clot that occurs naturally. It is broken down in the same way as an endogenous clot (from the body itself) and does not leave any residue. A synthetic protein (synthetic aprotinin) is added to increase the duration of the clot and prevent its premature breakdown.

What is TISSEEL used for

TISSEEL is used as an adjunctive treatment when conventional surgical methods seem insufficient:

• to improve hemostasis
• as a tissue sealant, to improve wound healing or to seal sutures in vascular surgery and in the gastrointestinal tract
• to adhere tissues, e.g., to attach skin grafts.

TISSEEL is also effective in patients receiving treatment with the anticoagulant heparin.

2. What you need to know before you start using TISSEEL

Do not use TISSEEL:

• if you are allergic to the active substances or to any of the other components of this medicine (listed in section 6).
• in case of severe arterial or venous bleeding. Single administration of TISSEEL is not indicated in this situation
• TISSEEL must not be injected into blood vessels (veins or arteries). As TISSEEL forms a clot at the site of administration, injection into a blood vessel can cause the formation of blood clots. If these clots are released into the bloodstream, they can cause potentially life-threatening complications
• TISSEEL is not intended to replace skin sutures made to close a surgical wound.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use TISSEEL.

Be particularly careful with TISSEEL as it can cause allergic hypersensitivity reactions.

Among the first symptoms of an allergic reaction may include:

• transient skin reddening
• itching
• hives
• nausea, vomiting
• general malaise
• chills
• chest tightness
• swelling of lips and tongue
• difficulty breathing/dyspnea
• drop in blood pressure
• increase or decrease in pulse rate

If these symptoms occur, the application should be interrupted immediately. Severe symptoms require urgent treatment.

• TISSEEL contains a synthetic protein known as aprotinin. Although this protein is applied only in small quantities and only to the surface of the wound, there is a risk of severe allergic reaction. The risk appears to increase in patients who have previously received TISSEEL or aprotinin, even if it was well tolerated during previous application. Therefore, any use of aprotinin or products containing aprotinin should be included in your medical history. Since synthetic aprotinin is structurally identical to bovine aprotinin, the use of TISSEEL in patients with allergies to bovine proteins should be carefully evaluated
• potentially life-threatening complications can occur if blood clots are released into the bloodstream due to accidental injection into a blood vessel.
• intravascular application may increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients. In particular, during coronary surgery, the doctor should be careful not to inject TISSEEL into a blood vessel. It is equally important to avoid injection into the nasal mucosa, as blood clots can occur in the area of the ophthalmic artery
• there is a risk of local tissue damage in case of injection into tissue
• to avoid tissue sealing in unwanted areas. Therefore, before administration, care should be taken to cover all parts of the body that are not the area to be treated
• the formation of an excessively thick fibrin clot can negatively affect the efficacy of the product and the wound healing process. Therefore, TISSEEL should be applied in a thin layer.

Caution should be exercised when applying a fibrin tissue adhesive using pressurized gas.

Very rare cases of gas embolism (air or gas) (introduction of air into the bloodstream, which can be serious or life-threatening) have occurred as a result of the use of spray devices with pressure regulators to apply fibrin tissue adhesives. These cases appear to be related to the use of spray equipment at pressures higher than recommended and/or at a very close distance to the tissue surface. The risk appears to be greater when fibrin tissue adhesives are sprayed with air, compared to CO2, and therefore cannot be excluded with TISSEEL when sprayed during surgical intervention of an open wound.

The spray devices and applicator tips include instructions for use that recommend pressure intervals and distance from the tissue surface.

TISSEEL should be administered exactly as specified in the instructions and only with the equipment recommended for this product.

Whenever TISSEEL is sprayed, changes in blood pressure, pulse, oxygen saturation, andCO2level at the end of expiration should be monitored to detect possible gas embolism.

When administering medicines derived from human plasma or blood, certain measures must be taken to prevent infections from being transmitted to patients. Such measures include:

• careful selection of donors to ensure that those at risk of being carriers of infectious diseases are excluded
• testing for specific infection/virus markers in individual donations and in plasma pools
• inclusion of stages in the manufacturing process that can eliminate/inactivate viruses.

Despite these measures, when administering medicines derived from human blood or plasma, the possibility of transmission of infection cannot be entirely excluded. This also applies to emerging or unknown viruses or other types of infections.

These measures are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and against the non-enveloped hepatitis A virus. The measures taken may have limited value against non-enveloped viruses, such as parvovirus B19. Parvovirus B19 infection can be severe for a pregnant woman (fetal infection) and for individuals whose immune system is depressed or for patients with certain types of anemia (e.g., sickle cell disease or hemolytic anemia).

Your doctor may recommend that you consider vaccination against hepatitis A and B if you are regularly or repeatedly administered fibrin sealants derived from human plasma.

It is strongly recommended that, each time a dose of TISSEEL is administered, a record be kept of the name of the medicine and batch number administered in order to maintain a record of the batches used.

Other medicines and TISSEEL

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those obtained without a prescription.

No interactions with other medicines are known.

As with similar products or thrombin solutions, the product may be damaged if it comes into contact with solutions containing alcohol, iodine, or heavy metals (e.g., antiseptic solutions). Care should be taken to eliminate these substances as much as possible before applying the product.

For information on preparations containing oxidized cellulose, see Handling and Preparation Instructions.

Using TISSEEL with food and drinks

Ask your doctor. Your doctor will decide if you can eat or drink before the application of TISSEEL.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine. Your doctor will decide if you can use TISSEEL during pregnancy or breastfeeding.

Driving and using machines

TISSEEL does not affect your ability to drive or use machines.

TISSEEL contains polysorbate 80

Polysorbate 80 may cause localized skin irritation, such as contact dermatitis.

3. How to use TISSEEL

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

Before applying TISSEEL, it is necessary to dry the wound surface using a standard technique (e.g., intermittent application of swabs, pledgets, or the use of suction devices).

Pressurized air or gas should not be used to dry the area.

TISSEEL should only be sprayed onto visible application areas.

When applying TISSEEL with a spray device, ensure that you use a pressure and distance to the tissue that are within the recommended range by the manufacturer as follows:

Whenever TISSEEL is sprayed, and due to the possibility of gas embolism (air or gas), changes in blood pressure, pulse, oxygen saturation, andCO2level at the end of expiration (see section 2) should be monitored.

The dose to be administered will depend on individual requirements.

The dose depends on a number of factors, such as the type of surgical procedure, the size of the affected surface, the method of application, and the number of applications. Your doctor will decide the appropriate amount and apply enough to form a thin layer over the lesion. If the amount seems insufficient, the application can be repeated.

When applying TISSEEL, coagulation occurs rapidly. Application of a new layer to an existing layer of TISSEEL should be avoided, as the new layer will not adhere to the existing one.

Separate application of the sealant protein component and the thrombin component should be avoided.

In clinical trials, individual doses of 4 to 20 ml were administered. Larger volumes may be necessary in some procedures (e.g., liver lesions or sealing of large burned surfaces).

As a guide for sealing surfaces, 1 package of TISSEEL (2 ml, 1 ml sealant protein solution plus 1 ml thrombin solution) will be sufficient, at least, for a surface area of 10 cm2.

When applying TISSEEL with a spray device, the same amount will be sufficient to cover considerably larger areas.

To avoid excessive granulation tissue formation and to ensure gradual degradation of the fibrin tissue adhesive, only a thin layer of TISSEEL should be applied.

To ensure adequate mixing of the sealant protein component and the thrombin component, the first drops of the product should be expelled and discarded from the applicator cannula immediately before use.

If you use more TISSEEL than you should

TISSEEL is only applied during surgical interventions. The doctor will determine the necessary amount. No cases of overdose are known.

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

Children

The safety and efficacy of the product in children have not been established.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. If you consider that any of the adverse effects you suffer from is serious or if you notice any adverse effect not mentioned in this prospectus, inform your doctor or pharmacist.

In patients treated with fibrin tissue adhesive, hypersensitivity reactions or allergic reactions may occur. Although they are rare, they can be serious.

The first symptoms of an allergic reaction may include:

• transient skin redness ("flushes")
• itching
• hives
• nausea, vomiting
• headache
• numbness
• restlessness
• burning and itching at the application site
• tingling
• chills
• chest tightness
• swelling of lips, tongue, throat (which can result in difficulty breathing and/or swallowing)
• difficulty breathing
• low blood pressure
• increase or decrease in pulse frequency
• loss of consciousness due to a drop in blood pressure

In isolated cases, these reactions can progress to severe allergic reactions (anaphylaxis). These reactions can occur especially if the preparation is applied repeatedly or if it is administered to patients who have previously shown hypersensitivity to aprotinin or any other component of the product.

Even if a repeated treatment with TISSEEL was well tolerated, a subsequent administration of TISSEEL or an aprotinin infusion may lead to severe allergic (anaphylactic) reactions.

The medical team treating you will be aware of the risk of this type of reaction and will stop the application of TISSEEL immediately upon appearance of the first symptoms of hypersensitivity. In case of severe symptoms, emergency measures may be necessary.

The injection of TISSEEL into soft tissues can cause local damage to these tissues.

The injection of TISSEEL into blood vessels (veins or arteries) can cause the formation of blood clots (thrombosis).

Since TISSEEL is manufactured from plasma from blood donations, the risk of infections cannot be completely excluded. However, manufacturers take numerous measures to reduce this risk (see section 2).

Rarely, antibodies against the components of the fibrin tissue adhesive may occur.

The following adverse effects have been observed during treatment with TISSEEL:

Adverse effects have been evaluated using the following frequency categories:

Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people

Uncommon: may affect up to 1 in 100 people

Rare: may affect up to 1 in 1,000 people

Very rare: may affect up to 1 in 10,000 people

Frequency not known: cannot be estimated from the available data.

*There have been cases of introduction of air bubbles or gas into the vascular system when applying fibrin sealants with spray devices that use gas or air under pressure; it is believed that the cause of this effect is the improper use of the spray equipment (e.g., at pressures higher than recommended and at a very close distance to the tissue surface).

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaram.es.

By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of TISSEEL

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date that appears on the packaging after "EXP".

Store and transport frozen (<-20 °C) without interruption until application.

Store the syringe in the outer packaging to protect it from light.

Storage after thawing:

The unopened product, thawed at room temperature, can be stored for up to 72 hours at controlled room temperature (not above 25 °C).

Once thawed, the solution must not be re-frozen or refrigerated!

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicine packages that are no longer needed. This will help protect the environment.

6. Package contents and additional information

Composition of TISSEEL

TISSEEL contains two components:

Component 1: Protein solution

The active ingredients in 1 ml of protein solution are: human fibrinogen, 91 mg/ml; synthetic aprotinin, 3000 UIC/ml.

The other components are: human albumin, L-histidine, niacinamide, polysorbate 80 (Tween 80), sodium citrate dihydrate, water for injectable preparations.

Component 2: Thrombin solution

The active ingredients in 1 ml of thrombin solution are: human thrombin 500 UI/ml; calcium chloride dihydrate 40 μmol/ml.

The other components are: human albumin, sodium chloride, water for injectable preparations.

TISSEEL contains 0.6–5 UI/ml of human factor XIII that is isolated from plasma along with human fibrinogen.

Appearance of the product and package contents

Solutions for tissue adhesive.

The protein solution and thrombin solution are supplied in a single-use plastic syringe.

The frozen solutions are colorless to pale yellow and opalescent.

After thawing: the liquids are colorless to pale yellow.

TISSEEL is supplied in the following packaging:

Package contents with the PRIMA syringe:

• 1ml, 2ml, or 5ml of protein solution and 1ml, 2ml, or 5ml of thrombin solution contained in a pre-loaded dual-chamber syringe (polypropylene) closed with a screw cap, packaged in two bags and with a device with two connecting pieces and 4 application cannulas.

Package contents with the AST syringe:

• 1ml, 2ml, or 5ml of protein solution and 1ml, 2ml, or 5ml of thrombin solution contained in a pre-loaded dual-chamber syringe (polypropylene) closed with a screw cap, packaged in two bags and with a device with two connecting pieces, 4 application cannulas, and a double-piston plunger.

Package sizes:

TISSEEL is available in the following package sizes: 1 x 2 ml (1 ml + 1 ml), 1 x 4 ml (2 ml + 2 ml), and 1 x 10 ml (5 ml + 5 ml).

The solutions are frozen.

Not all package sizes may be marketed.

Marketing authorization holder and manufacturer:

Marketing authorization holder:

BAXTER, S.L.

Pouet de Camilo, 2

46394 Ribarroja del Turia (Valencia)

Manufacturer:

Takeda Manufacturing Austria AG,

Industriestrasse 67,

1221 Vienna, Austria

This medicine is authorized in the Member States of the European Economic Area under the following names:

Austria:TISSEEL - Lösungen für einen Gewebekleber

Bulgaria:T???? - ???????? ?? ??????? ??????

Czech Republic:TISSEEL - roztoky pro lepidlo

France:TISSEEL –solutions pour colle

Germany:TISSEEL 2ml

TISSEEL 4ml

TISSEEL 10ml

Greece:TISSEEL - Διαλ?ματα για στεγανοποιητικ?

Malta:TISSEEL – Solutions for sealant

Norway:TISSEEL

Poland:TISSEEL - klej tkankowy

Slovak Republic:TISSEEL – fibrinové lepidlo

Spain:TISSEEL – soluciones para adhesivo tisular

Date of last revision of this prospectus: August 2020

Detailed information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)

This information is intended only for healthcare professionals (final packaging: PRIMA syringe):

General

• Before administering TISSEEL, all parts of the body outside the area to be treated should be covered to prevent tissue adhesion in unwanted areas.

• To avoid TISSEEL adhering to gloves and surgical instruments, they should be moistened with a sodium chloride solution before coming into contact with TISSEEL.

• The guideline for surface sealing is: one 2 ml package of TISSEEL (1 ml of sealant protein solution plus 1 ml of thrombin solution) is sufficient for a surface area of at least 10 cm2.

• The required dose will depend on the size of the surface to be sealed.

• DO NOT apply the two components of TISSEEL separately. Both components must be applied together.

• DO NOT expose TISSEEL to temperatures above 37 °C and DO NOT heat in a microwave.

• DO NOT thaw the product by holding it in your hands.

• DO NOT use TISSEEL until it has been completely thawed and warmed to 33 °C-37 °C.

• The protective caps of the syringe should only be removed when thawing and warming are complete. To facilitate the removal of the syringe cap, it should be rocked back and forth and then the protective cap removed.

• Expel all air from the syringe and connect the union nozzle and application cannula.

Handling and Preparation Instructions

Both the sealant protein solution and the thrombin solution are contained in a ready-to-use syringe. The product is packaged in two sterile bags under aseptic conditions. The inner bag and its contents are sterile as long as the outer bag is intact. Using a sterile technique, transfer the inner sterile bag and its contents to the sterile field.

The ready-to-use syringe can be thawed and warmed using one of the following methods:

1. Rapid thawing/warming (sterile water bath),recommended method
2. Thawing/warming in a non-sterile water bath
3. Thawing/warming in an incubator
4. The ready-to-use syringe can also be thawed and stored at room temperature (not above 25 °C) for up to 72 hours. It must be warmed before use.

1. Rapid thawing/warming (sterile water bath), recommended method

It is recommended to thaw and warm the two components of the tissue adhesive using a sterile water bath at a temperature of 33–37 °C.

• The water bath should not exceed 37 °C. To control the specified temperature range, the water temperature should be monitored using a thermometer and the water changed as necessary.
• If a sterile water bath is used for thawing and warming, remove the pre-filled syringe from the bags before placing it in the sterile water bath.

Instructions:

Place the inner bag in the sterile field, remove the ready-to-use syringe from the inner bag, and place it directly in the sterile water bath. Ensure that the contents of the ready-to-use syringe are completely submerged in the water.

Table 1: PRIMA Syringe: Minimum Thawing and Warming Times Using a Sterile Water Bath

1. Thawing/warming in a non-sterile water bath

Instructions:

Leave the ready-to-use syringe in both bags and place it in a water bath outside the sterile field for an appropriate period of time (see Table 2). Ensure that the bags remain submerged in the water during the entire thawing period. After thawing, remove the bags from the water bath, dry the outer bag, and place the inner bag with the ready-to-use syringe in the sterile field.

Table 2: PRIMA Syringe: Minimum Thawing and Warming Times Using a Non-Sterile Water Bath

1. Thawing/warming in an incubator

Instructions:

Leave the ready-to-use syringe in both bags and place it in an incubator outside the sterile field for an appropriate period of time (see Table 3). Once thawed and warmed, remove the bags from the incubator, remove the outer bag, and place the inner bag with the ready-to-use syringe in the sterile field.

Table 3: PRIMA Syringe: Minimum Thawing and Warming Times in an Incubator

1. Thawing at room temperature (not above 25 °C) BEFORE warming

Instructions:

Leave the ready-to-use syringe in both bags and thaw it at room temperature outside the sterile field for an appropriate period of time (see Table 4). Once thawed, warm it in the outer bag in an incubator to warm the product for use.

Table 4: PRIMA Syringe: Minimum Thawing Times at Room Temperature Outside the Sterile Field and Additional Warming Times in an Incubator at 33 °C to 37 °C

After thawing at room temperature, the product must be used within 72 hours of removal from the refrigerator.

Stability after Thawing

After thawingand warming(at temperatures between 33 °C and 37 °C, methods 1, 2, and 3), the chemical and physical stability of the product has been demonstrated for 12 hours at 33-37 °C.

In the case of the product thawedat room temperature, in the unopened bag (method 4), the chemical and physical stability of the product has been demonstrated for 72 hours at temperatures not exceeding 25 °C. Warm to 33-37 °C immediately before use.

From a microbiological point of view, unless the opening/thawing method excludes the risk of microbial contamination, the product should be used immediately after warming to 33 °C to 37 °C.

If not used immediately, the times and conditions of storage during use are the responsibility of the user.

Do not re-freeze or refrigerate once thawing has begun.

Handling after Thawing/Before Application

To achieve optimal mixing of the two solutions and optimal solidification of the fibrin sealant, keepthe two components of the tissue adhesiveat 33-37 °C until application.

The sealant protein solution and thrombin solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. The thawed product should be visually inspected before use to rule out the presence of particles and discoloration or any variation in appearance. If any of these circumstances are observed, the solutions should be discarded.

The thawed sealant protein solution should be a slightly viscous liquid. If the solution has the consistency of a solidified gel, it should be assumed that it has denatured (possibly due to interruption of the cold chain or excessive heat during warming). In this case, TISSEEL SHOULD NOT be used in any way.

• Remove the syringe from the bags shortly before use.
• Use TISSEEL only when it has been completely thawed and warmed (liquid consistency).

• Remove the syringe cap immediately before application.

To facilitate the removal of the syringe cap, it should be rocked back and forth and then the protective cap removed.

Administrationwith PRIMA Syringe:

For application, the ready-to-use double-chamber syringe with the sealant protein solution and thrombin solution must be connected to a union nozzle and an application cannula provided in the application device kit. The piece that connects the plungers of the ready-to-use double-chamber syringe ensures that equal volumes of the two components of the tissue adhesive will exit through the union nozzle to the application cannula where they will mix before application.

PRIMA Syringe Operating Instructions:

• Expel all air from the syringe before connecting any application device.
• Align the union nozzle and anchor it to the side of the syringe at the anchor band hole.
• Connect the nozzles of the ready-to-use double-chamber syringe to the union nozzle, ensuring that both are firmly attached.

• Secure the union nozzle by fixing the anchor band to the ready-to-use double-chamber syringe.
• If the anchor band is torn, use the spare union nozzle provided in the kit.
• If no spare union nozzle is available, the system can still be used if care is taken to ensure that the connection is secure and leak-proof.
• DO NOT expel the air remaining in the union nozzle.

• Connect an application cannula to the union nozzle.

• DO NOT expel the air remaining in the union nozzle and the application cannula until application starts, as this may clog the cannula opening.

Administration

Before applying TISSEEL, the wound surface should be dried using a standard technique (e.g., intermittent application of swabs, pledgets, or the use of suction devices). Do not use compressed air or gas to dry the area.

• Apply the sealant protein solution-thrombin solution mixture to the surface or surfaces to be sealed by slowly pressing the rear of the common plunger.
• In surgical procedures that require the use of minimal volumes of fibrin sealant, it is recommended to expel and discard the first drops of the product.
• After applying TISSEEL, wait at least 2 minutes to achieve sufficient polymerization.

Note:If the application of the tissue adhesive components is interrupted, clots may form in the cannula. In this case, immediately replace the application cannula with a new one before resuming application. If the openings of the union nozzle become clogged, use the additional union nozzle provided in the package.

After mixing the components of the tissue adhesive, the fibrin sealant begins to set in a few seconds due to the high concentration of thrombin (500 UI/ml).

The fibrin sealant can also be applied with other accessories supplied by BAXTER that are specifically suitable for, e.g., endoscopic use, minimally invasive surgery, or application to large or difficult-to-access areas. When using these application devices, their instructions for use must be carefully followed.

Preparations containing oxidized cellulose should not be used with TISSEEL, as the low pH interferes with thrombin activity.

In certain applications, biocompatible materials, such as collagen sheets, are used as support material or for reinforcement.

Spray Application

When applying TISSEEL with a spray device, ensure that the pressure and distance to the tissue are within the recommended ranges specified by the manufacturer, as follows:

Whenever TISSEEL is sprayed, and due to the possibility of gas embolism (air or gas), changes in arterial pressure, pulse, oxygen saturation, and end-tidal CO2level should be monitored (see section 2).

For the application of TISSEEL in closed thoracic and abdominal cavities, the DuploSpray MIS application system is recommended. Consult the DuploSpray MIS device instruction manual.

Disposal

Disposal of unused medicinal products and waste materials should be carried out in accordance with local regulations.