Prospect: information for the user

TISSEEL Tissue Adhesive Solutions

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

Read this prospect carefully before starting to use this medication, as it contains important information for you.

–Keep this prospect, as you may need to read it again.

–If you have any doubts, consult your doctor or pharmacist.

–If you experience adverse effects, consult your doctor, pharmacist, or nurse, even if they do not appear in this prospect. See section 4.

1.What is TISSEEL and what it is used for

2.What you need to know before starting to use TISSEEL

3.How to use TISSEEL

4.Possible adverse effects

5.Storage of TISSEEL

6.Contents of the package and additional information

What isTISSEEL

TISSEELis a two-component tissue adhesive consisting of two solutions, the sealing 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 application site.

The clot produced by TISSEEL is very similar to the natural clot produced. It degrades in the same way as an endogenous clot (from the body) and does not leave residues. A synthetic protein (synthetic aprotinin) is added to increase the duration of the clot and prevent premature degradation.

What is TISSEEL used for

TISSEELis used as a complementary treatment when conventional surgical methods appear to be insufficient:

• to improve hemostasis
• as a tissue sealant, to improve wound healing or 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 heparin anticoagulant treatment.

No use TISSEEL:

• if you are allergic to the active ingredients or any of the other components of this medication (listed in section 6).
• in intense arterial or venous bleeding. A single administration of TISSEEL is not indicated in this situation.
• TISSEEL should not be injected into blood vessels (veins or arteries). As TISSEEL forms a clot at the site of administration, injecting it into a blood vessel may cause the formation of blood clots. If these clots are released into the bloodstream, they may cause potentially fatal complications.
• TISSEEL is not indicated to replace sutures of the skin made to close a surgical wound.

Warnings and precautions

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

Be especially careful with TISSEEL because hypersensitivity allergic reactions may occur.

The first symptoms of an allergic reaction may include:

If these symptoms appear, discontinue application immediately. Severe symptoms require urgent treatment.

• TISSEEL contains a synthetic protein known as aprotinin. Although this protein is applied in small quantities and only on 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 the 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 fatal complications may 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 especially careful not to inject TISSEEL into a blood vessel. It is equally important to avoid injection into the nasal mucosa as blood clots may form in the area of the ophthalmic artery.
• there is a risk of local tissue damage in the event of injection into tissue.
• to avoid sealing tissues in undesired areas. Therefore, before administration, all parts of the body that are not the area to be treated should be carefully covered.
• the formation of an excessively thick fibrin clot may negatively affect the efficacy of the product and the wound healing process. Therefore, TISSEEL should be applied in a thin layer.

Be careful when applying a fibrin tissue adhesive using a pressurized gas.

Very rare cases of gas embolism (air or gas introduction into the bloodstream that may be severe or life-threatening) have been reported as a result of using spray equipment 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 a surgical procedure on an open wound.

The spray equipment and applicator tip include usage instructions that recommend pressure intervals and the distance from the tissue surface at which to spray.

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

Whenever TISSEEL is sprayed, monitor changes in blood pressure, pulse, oxygen saturation, and CO2 level at the end of exhalation to detect a possible gas embolism.

When administering plasma-derived or blood-derived medications, certain measures should be taken to prevent the transmission of infections to patients. These measures include:

• a careful selection of donors to ensure that those at risk of being carriers of infectious diseases are excluded
• analysis of specific infection/virus markers in individual donations and plasma mixtures
• inclusion of stages in the manufacturing process that may eliminate/inactivate viruses

Despite these measures, when administering plasma-derived or blood-derived medications, 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 taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and for non-enveloped viruses such as 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 with immunosuppressed systems or 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 regularly or repeatedly receive fibrin sealants derived from human plasma.

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

Other medications and TISSEEL

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication, including those obtained without a prescription.

No interactions with other medications are known.

As with similar products or antiseptic 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, seeInstructions for handling and preparation.

Use of TISSEEL with food and beverages

Ask your doctor. Your doctor will decide if you can eat or drink before applying TISSEEL.

Pregnancy, breastfeeding, and fertility

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

Driving and operating machinery

TISSEEL does not affect your ability to drive or operate machinery.

Tisseel contains polisorbato 80

Polisorbato 80 may cause localized skin irritation such as contact dermatitis.

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

Before applying TISSEEL, the wound surface must be dried using a standard technique (e.g., intermittent application of compresses, sponges, or the use of suction devices).

Air or pressurized 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 the pressure and distance to the tissue are within the recommended range provided by the manufacturer as follows::

When spraying TISSEEL, and due to the possibility of gas embolism (air or gas), monitor changes in blood pressure, pulse, oxygen saturationand CO2 levels at the end of exhalation (see section 2).

The dose to be administered will always depend on your individual needs.

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

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

Avoid applying the protein sealant component and the thrombin component separately.

In clinical trials, individual doses of 4 to 20mlwere administered.You may need to apply larger volumes in some procedures (e.g., liver injuries or sealing large burn surfaces).

As a guide for surface sealing, one TISSEEL2ml pack (1ml of protein sealant solutionplus1ml of thrombin solution) will be sufficient, at a minimum, for a surface area of 10cm2.

When applying TISSEEL with aspray device,the same amount will be sufficient to coverconsiderably larger areas.

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

To ensure a suitable mixture of the protein sealant component and the thrombin component, the first few drops of the product from the application cannula should be expelled and discarded immediately before use.

If you use more TISSEELthan you should

TISSEELis only applied during surgical interventions. Your doctor will determine the necessary amount. No cases of overdose are known.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Children

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them. If you consider that any of the side effects you experience are severe or if you notice any side effect not mentioned in this leaflet, inform your doctor or pharmacist.

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

The first symptoms of an allergic reaction may include:

• Transient skin redness ("flushing")
• Itching
• Hives
• Nausea, vomiting
• Headache
• Numbness
• Restlessness
• Burning and itching at the application site
• Tickling
• Chills
• Pressure in the chest
• Swelling of the lips, tongue, throat (which may result in difficulty breathing and/or swallowing)
• Difficulty breathing
• Low blood pressure
• Increased or decreased heart rate
• Loss of consciousness due to a drop in blood pressure

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

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

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 the appearance of the first symptoms of hypersensitivity. In case of severe symptoms, emergency measures may be necessary.

The injection of TISSEEL into soft tissues may damage them locally.

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

As TISSEEL is manufactured from plasma derived from blood donations, the risk of infections cannot be entirely ruled out. However, manufacturers take numerous measures to reduce this risk (see section 2).

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

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

Side 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 available data.

*Cases of introduction of gas or air bubbles into the vascular system have been reported when fibrin sealants are applied 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 device (e.g., at pressures higher than recommended and at a very close distance to the tissue surface).

Reporting of side effects

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

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

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

Do not use this medication after the expiration date that appears on the packaging after “CAD”.

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 to room temperature, can be stored for up to 72 hours at controlled room temperature (not exceeding 25 °C).

Once thawed, the solution should not be refrozen or refrigerated!

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging of medications that you no longer need. This will help protect the environment.

Composition ofTISSEEL

TISSEEL contains two components:

Component 1: Fibrin sealant solution

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

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

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 injection.

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

Appearance of the product and contents of the package

Fibrin sealant solutions.

The fibrin sealant 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 package:

Contents of the package with the PRIMA syringe:

• 1ml, 2ml or 5ml of fibrin sealant solution and 1ml, 2ml or 5ml of thrombin solution contained in a preloaded double-chamber syringe (polpropylene) closed with a screw cap, packaged in two pouches and with a two-piece connector and 4 application cannulas.

Contents of the package with the AST syringe:

• 1ml, 2ml or 5ml of fibrin sealant solution and 1ml, 2ml or 5ml of thrombin solution contained in a preloaded double-chamber syringe (polpropylene) closed with a screw cap, packaged in two pouches and with a two-piece connector, 4 application cannulas and a double piston plunger.

Package sizes:

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

The solutions are frozen.

Only some package sizes may be commercially available.

Marketing authorization holder and responsible person for manufacturing:

Marketing authorization holder:

BAXTER, S.L.

Pouet de Camilo, 2

46394 Ribarroja del Turia (Valencia)

Responsible person for manufacturing:

Takeda Manufacturing Austria AG,

Industriestrasse 67,

1221 Vienna, Austria

This medicinal product is authorized in the member states of the European Economic Area with 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?ματαγιαστεγανοποιητικ?

Malta:TISSEEL – Solutions for sealant

Norway:TISSEEL

Poland:TISSEEL - klej tkankowy

Slovak Republic:TISSEEL – fibrinové lepidlo

Spain:TISSEEL – soluciones para adhesivo tisular

Final date of the last revision of this leaflet: August 2020

This information is intended solely for healthcare professionals (final package: PRIMA syringe):

General

• Before administering TISSEEL, all parts of the body outside the area to be treated must be covered to prevent unwanted adhesion of tissues.

• To prevent TISSEEL from adhering to gloves and surgical instruments, these must be moistened with a sodium chloride solution before contact occurs.

• The guide for sealing surfaces is: a TISSEEL 2 ml package (1 ml of fibrin sealant solutionplus1 ml of thrombin solution) is sufficient for a surface 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 thawed completely and been warmed to 33°C-37°C.

• The protective caps of the syringe must only be removed when thawing and warming have been completed. To facilitate the removal of the cap from the syringe, it must be gently rocked back and forth, and then the protective cap of the syringe must be removed.

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

Instructions for handling and preparation

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

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

1. Thawing and warming quickly (sterile water bath),recommended method
2. Thawing and warming in a non-sterile water bath
3. Thawing and 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 72hours. It must be warmed before use.

1) Thawing and warming quickly (sterile water bath),recommended method

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

• The water bathmust notexceed 37 °C. To control the specified temperature range, the water temperature must be monitored using a thermometer and the water changed as necessary.
• If a sterile water bath is used for thawing and warming, remove the preloaded syringe from the pouches before placing it in the water bath.

Instructions:

Place the inner pouch in the sterile field, remove the ready-to-use syringe from the inner pouch 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

2) Thawing and warming in a non-sterile water bath

Instructions:

Leave the ready-to-use syringe in both pouches and place it in a non-sterile water bath outside the sterile field for an adequate period of time (see Table2). Ensure that the pouches remain submerged in the water during the entire thawing period. After thawing, remove the pouches from the water bath, dry the outer pouch and place the inner pouch 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

3) Thawing and warming in an incubator

Instructions:

Leave the ready-to-use syringe in both pouches and place it in an incubator outside the sterile field for an adequate period of time (see Table3). Once thawed and warmed, remove the pouches from the incubator, remove the outer pouch and place the inner pouch with the ready-to-use syringe in the sterile field.

Table 3: PRIMA syringe: Minimum thawing and warming times in an incubator

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

Instructions:

Leave the ready-to-use syringe in both pouches and thaw it at room temperature outside the sterile field for an adequate period of time (see Table4). Once thawed, warm it in the outer pouch 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 of 33 °C to 37 °C

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

Stability after thawing

Afterthawingand 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 productthawedat room temperature, in the unopened pouch (method4), the chemical and physical stability of the product has been demonstrated for72 hours at temperatures not exceeding 25ºC.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 must be used immediately, after having been warmed from 33ºC to 37ºC.

Unless used immediately, the storage times and conditions 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 an optimal mixture of the two solutions and optimal solidification of the fibrin tissue sealant,keepthe two components of the fibrin tissue sealant at 33-37 °C until application.

The fibrin sealant solution and thrombin solution must be transparent or slightly opalescent. Do not use solutions that are turbid or have deposits. The thawed product must be visually inspected before use to discard the presence of particles and discoloration or any variation in appearance. If you observe any of these circumstances, the solutions must be discarded.

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

• Remove the syringe from the pouches just before using it.
• Use TISSEEL only when it has thawed and warmed completely (liquid consistency).

• Remove the protective cap from the syringe immediately before application.

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

Administrationwith PRIMA syringe:

To apply TISSEEL, the ready-to-use syringe with the fibrin sealant solution and thrombin solution must be connected to a connector and application cannula provided in the application device kit. The piece that connects the plungers of the ready-to-use syringe ensures that equal volumes of the two components of the fibrin tissue sealant will exit through the connector and into the application cannula, where they will mix before application.

Instructions for the operation of the PRIMA syringe:

• Expel all air from the syringe before connecting any application device.
• Align the connector and secure it to the side of the syringe in the banding clip.
• Connect the plungers of the ready-to-use syringe to the connector, ensuring that both are securely attached.

• Secure the connector by fixing the banding clip to the ready-to-use syringe.
• If the banding clip tears, use the spare connector provided in the kit.
• If no spare connector is available, the system can still be used if the connection is secure and leak-proof.
• DO NOT expel the air remaining in the connector.

• Connect an application cannula to the connector.

• DO NOT expel the air remaining in the connector and application cannula until application begins, as this can block the opening of the cannula.

Administration

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

• Apply the mixture of fibrin sealant solution-thrombin solution to the surface or surfaces of the parts to be sealed by slowly pushing the common plunger.
• In surgical procedures that require the use of minimal volumes of fibrin tissue 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 components of the fibrin tissue sealant is interrupted,coagula may form in the cannula. In this case, immediately replace the application cannula with a new one before reapplying the product. If the openings of the connector become blocked, use the spare connector provided in the package.

After mixing the components of the fibrin tissue sealant, the fibrin tissue sealant begins to settle in a few secondsdue tothe high concentration of thrombin (500UI/ml).

The fibrin tissue sealant can also be applied with other accessories provided by BAXTER that are specifically designed for, e.g., endoscopic use, minimally invasive surgery or application in large or hard-to-reach areas. When using these application devices, follow theirinstructions for use.

Do not use preparations containing oxidized cellulose with TISSEEL,because the low pH interferes with the activity of thrombin.

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

Application by spraying

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

When spraying TISSEEL, and due to the possibility of gas embolism (air or gas), monitor changes in blood pressure, pulse, oxygen saturation and CO2level at the end of expiration (see section 2).

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

Disposal

The disposal of unused medicinal product and waste materials,will be carried out in accordance with local regulations.