Product Information for the User

ARTISS

Tissue Adhesive Solutions

Ultraconcentrated

Human Fibrinogen, Human Thrombin, Aprotinin, Calcium Chloride Dihydrate

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

• Keep this product information, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this product information. See section 4.

What is ARTISS

ARTISS is a two-component fibrin sealant that contains two of the proteins that allow blood to clot. These proteins are called fibrinogen and thrombin. When these proteins are mixed during application, they form a clot at the site where the surgeon applies them.

ARTISS is prepared as two solutions (protein sealant solution and thrombin solution), which are mixed when applied.

How ARTISS is used

ARTISS is a tissue adhesive.

ARTISS is applied to seal soft tissues in plastic, reconstructive, or burn surgery.

For example, ARTISS can be used to attach skin grafts or skin flaps to wounds caused by burns or to attach skin to underlying tissue in plastic surgery. ARTISS can also attach artificial skin to wounds.

The clot produced by ARTISS is very similar to the natural clot that forms.

This means that it will dissolve naturally without leaving any residue. However, aprotinin (a protein that delays the dissolution of clots) is added to increase the duration of the clot and prevent premature dissolution.

No use ARTISS:

• If you are allergic to the active ingredients or to any of the other components of this medication (listed in section 6).
• Do not use ARTISS in cases of massive or rapid bleeding.
• ARTISS is not indicated to replace skin sutures performed to close a surgical wound.
• DO NOT INJECT ARTISS into blood vessels (veins or arteries) or tissues. As ARTISS forms a clot when applied, injecting ARTISS may cause severe reactions (e.g. vessel occlusion). ARTISS should only be applied to the surface of tissues as a thin layer where needed.
• Do not receive ARTISS if you are allergic (hypersensitive) to the active ingredients, bovine proteins, or any of the other components (see section 6) of ARTISS. It may cause severe allergic reactions.

Inform your doctor or surgeon if you know you are allergic to aprotinin or any bovine protein.

•ARTISS should not be applied by spraying in endoscopic procedures. For laparoscopic procedures (minimally invasive surgery), see the section “Warnings and precautions”.

Warnings and precautions

• Consult your doctor, pharmacist, or nurse before starting to use Artiss.
• There have been cases of gas embolism (air or gas introduction into the bloodstream that may be fatal or life-threatening) as a consequence of using spray applicators with pressure regulators to apply fibrin tissue adhesives. These cases seem 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 ruled out with ARTISS.
• When applying ARTISS with a spray applicator, ensure that both the pressure and distance of spraying are within the recommended range by the manufacturer. ARTISS should be administered exactly as specified in the instructions and only with the recommended equipment for this product.
• Whenever ARTISS is sprayed, monitor changes in blood pressure, pulse, oxygen saturation, andend-tidal CO2 levelto detect possible gas embolism.
• Do not use ARTISS with the Easy Spray/Spray Set in confined anatomical spaces due to serious safety reasons.
• Artiss is not recommended for laparoscopic surgery (minimally invasive surgery).

• ARTISS should only be applied with equipment bearing the CE mark.
• If accessory nozzles are used with this product, follow the usage instructions for the nozzles.

• If you have ever received ARTISS or aprotinin, your body may have developed sensitivity. You may be allergic to this material even if you had no reaction to the first application. Inform your doctor if you believe you received one of the products in a previous operation.
• If there is any sign of allergic reaction, your doctor will immediately stop the application of ARTISS and give you the appropriate treatment.
• Artiss is not indicated to stop bleeding or for sealing in situations where rapid coagulation of the sealant is required. Especially, Artiss should not be used in cardiac surgery procedures where the goal is to seal surgical connections of blood vessels.
• ARTISS is not indicated for use in neurosurgery or as a suture support in cases of gastrointestinal or vascular anastomosis since there are no available data to support these indications.

• Before administering ARTISS, the external parts of the body outside the application area should be sufficiently protected/covered to prevent any unwanted tissue adhesion.
• ARTISS is applied as a thin layer. An excessively thick clot may negatively affect the product's efficacy and the wound healing process.
• Your doctor will not use preparations containing oxicelulosa as a transport material since they may reduce the efficacy of Artiss.

When administering plasma-derived or blood-derived medications, certain measures should be taken to prevent infections from being passed to patients. Such measures include:

• a careful selection of donors, excluding those at risk of being carriers of infectious diseases,
• analysis of specific infection markers in individual donations and plasma mixtures,
• as well as inclusion of stages in the manufacturing process to eliminate/inactivate viruses.

Despite this, when administering blood or plasma-derived medications, the possibility of transmission of infectious agents cannot be entirely ruled out. This also applies to emerging or unknown viruses or other types of infections. These measures 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 a compromised immune system or patients with certain types of anemia (e.g. sickle cell disease or hemolytic anemia).

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

Use of ARTISS with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

ARTISS can be used at the same time as other medications. No interactions between ARTISS and other medications are known. As with similar products or thrombin solutions, the product may denature if exposed to solutions containing alcohol, iodine, or heavy metals (e.g. antisepsis solutions). Care should be taken to eliminate such substances as much as possible before applying the product.

Use of ARTISS with food and beverages

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

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or if you believe you may be pregnant, consult your doctor before using this medication. Your doctor will decide if ARTISS can be used during pregnancy and breastfeeding.

Driving and operating machinery

ARTISS will not affect your ability to drive or operate other types of machinery.

·ARTISS should only be administered during the surgical procedure. The use of ARTISS is

limited to experienced surgeons who have been properly trained on the use of ARTISS.

·The amount of ARTISS to be applied depends on various factors, such as the type of

surgery, the size of the tissue surface to be treated during your operation, and the method

of ARTISS application. The surgeon will decide on the appropriate amount.

·During your operation, the surgeon will apply ARTISS to the specific tissue using the

special application equipment provided. This equipment ensures that equal amounts of the

two components of the fibrin adhesive are applied at the same time, which is important for

achieving optimal results with ARTISS.

·Before applying ARTISS, it is necessary to dry the wound surface using a standard technique

(for example, intermittent application of compresses, sponges, or the use of suction devices).

ARTISS should only be sprayed onto visible application areas.

·It is recommended that the initial application cover the entire surface area to be treated.

When applying ARTISS with a spray gun, ensure that the pressure and distance to the tissue

are within the recommended ranges provided by the manufacturer, as indicated below:

Whenever ARTISS is sprayed, and due to the possibility of gas embolism (air or gas), monitorchanges in blood pressure, pulse, oxygen saturation, and CO2 levels at the end of exhalation(see section 2).

If you use more ARTISS than you should

Only ARTISS will be applied during a surgical procedure. It will be applied by a surgeon, and the

amount of ARTISS will be determined by the surgeon.

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

Like all medicines, this medicine may cause side effects, although not everyone will experience them. The following table explains the meaning of each frequency, as provided in the following section:

• There is a slight possibility that you may have an allergic reaction to one of the components of ARTISS (see section 6). This is more likely if you have been given ARTISS or aprotinin during a previous operation. Allergic reactions can be serious, so it is very important that you discuss this possibility with your doctor.
• Allergic reactions of anaphylactic/anaphylactoid type, of unknown frequency, may occur. The first symptoms of allergic reactions may be: hot flushes, low blood pressure, increased or decreased pulse, nausea (feeling unwell), hives, itching, difficulty breathing.
• The surgical team treating you should be aware of the risk of this type of reaction and, if they observe any of these symptoms, they will stop applying ARTISS immediately. Severe symptoms may require emergency treatment. The frequency of allergic reactions is unknown.
• If ARTISS is injected into soft tissues, it may damage local tissues. Unknown frequency.
• If ARTISS is injected into blood vessels (veins or arteries), blood clots (thrombosis) may occur. Unknown frequency.

• As ARTISS is made from plasma derived from blood donations, the risk of infection cannot be completely ruled out, although the manufacturer takes numerous measures to reduce the risk (see section 2).
• Cases of gas embolism (air or gas) that may put your life at risk or be fatal (introduction of air into the bloodstream that may be serious or life-threatening) have occurred as a result of using pressure-regulating equipment to apply fibrin tissue adhesives. These cases appear to be related to the use of the pressure-regulating equipment at pressures higher than recommended and/or at a very close distance to the tissue surface.

Adverse reactions reported during clinical trials of Artiss and during post-marketing experience with fibrin tissue adhesives from Baxter are described below. The known frequencies of these adverse reactions are based on a controlled clinical trial conducted in 138 patients where ARTISS was used to fix skin grafts in areas without skin due to burns. None of these events observed in the clinical trial were classified as severe.

*Cases of gas embolism (air or gas) entering the vascular system have occurred when fibrin tissue adhesives are applied using pressure-regulating equipment that uses gas or air under pressure; it is believed that the cause of this effect is the improper use of the pressure-regulating equipment (e.g., at pressures higher than recommended and at a very close distance to the tissue surface).

The following adverse reactions have been reported for other fibrin adhesives; their frequencies cannot be provided: allergy, severe allergic reaction, decreased heart rate, increased heart rate, decreased blood pressure, hemorrhage, difficulty breathing, discomfort, hives, redness, alterations in wound healing, inflammation, fever, accumulation of lymph and other transparent body fluids under the skin and near the surgical site.

Reporting of adverse reactions

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

By reporting adverse reactions, 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 ARTISS after the expiration date that appears on the packaging after “CAD”.
• Store and transport frozen (at -20°C) without interruption until preparation for application.
• Store ARTISS in the original packaging to protect it from light.

Conservation after thawing:

Thawed bags at room temperature without opening can be stored for up to 14 days in a controlled room temperature (not exceeding +25°C).

Once thawed, do not re-freeze or refrigerate!

Medicines should not be disposed of through drains or trash. Ask your pharmacist how to dispose of packaging and unused medications. This will help protect the environment.

ARTISS contains two components:

Component 1 = Fibrin Sealant Solution:

The active principles contained in 1 ml of fibrin sealant solution are:

Human fibrinogen, 91 mg/ml produced from human donor plasma; synthetic aprotinin, 3000 UIC/ml.

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

Component 2 = Thrombin Solution:

The active principles contained in 1 ml of thrombin solution are:

Human thrombin, 4 UI/ml produced from human donor plasma; calcium chloride dihydrate, 40 mmol/ml.

The other components are human albumin, sodium chloride, and water for injection.

ARTISS contains human factor XIII copurified with human fibrinogen in a range of 0.6 - 5 UI/ml.

Appearance of the product and contents of the package

Topical tissue adhesives.

Frozen solutions for topical tissue adhesives (fibrin sealant solution of 1 ml, 2 ml or 5 ml and thrombin solution of 1 ml, 2 ml or 5 ml in a single-use dual-chamber syringe contained in a pouch). Unit package.

Contents of the package with PRIMA syringe:

1 ml, 2 ml or 5 ml of fibrin sealant solution and 1 ml, 2 ml or 5 ml of thrombin solution in a single-use dual-chamber preloaded syringe (polypropylene) closed with a screw cap, packaged in two pouches and with a device with 2 connection nozzles and 4 application cannulas.

Contents of the package with AST syringe:

1 ml, 2 ml or 5 ml of fibrin sealant solution and 1 ml, 2 ml or 5 ml of thrombin solution in a single-use dual-chamber preloaded syringe (polypropylene) closed with a screw cap, packaged in two pouches and with a device with a double syringe plunger, 2 connection nozzles, 4 application cannulas.

The solution is colorless or pale yellow.

Only some package sizes may be marketed.

Marketing authorization holder

BAXTER, S.L.

Pouet de Camilo, 2

46394 Ribarroja del Turia (Valencia)

Phone: 962 722 800

Fax: 962 722 795

Responsible for manufacturing

Takeda Manufacturing Austria AG

Industriestraße 67

A-1221 Vienna

Austria

This medicinal product is authorized in the member states of the European Economic Area with the following names:

ARTISSin the following countries: AT, BE, CZ, DE, EL, ES, FI, FR, IE, IT, LU, NL, NO, PL, PT, UK.

Artissin DK, IS, SE.

Latest revision date of this leaflet: April 2021

The detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

---------------------------------------------------------------------------------------------------------------

This information is intended solely for medical professionals or healthcare professionals:

Fertility, pregnancy, and lactation

No safety data are available for the use of fibrin adhesives/hemostatics in pregnant women or in lactating women in controlled clinical trials. No animal studies have been performed.

Therefore, the product should not be administered to pregnant women or lactating women unless absolutely necessary.

The effects of ARTISS on fertility have not been established.

Dosage and administration

ARTISS is only for hospital use. The use of ARTISS is limited to experienced surgeons who have been properly trained in the use of ARTISS.

Dosage

The amount of ARTISS to be applied and the frequency of application should always be directed towards the underlying clinical needs of the patient.

The dose to be applied depends on some variables such as the type of surgical intervention, the size of the area, the method of application, and the number of applications, among others.

The doctor should individualize the application of the product. In clinical trials, individual doses have usually ranged from 0.2 to 12 ml..It may be necessary to administer larger volumes in some procedures (e.g., sealing large burned surfaces).

A sufficient amount of product should be applied to the anatomical area or surface to be treated to cover the desired area of application. If necessary, the application can be repeated in small areas that could not be treated previously. However, it should be avoided to reapply ARTISS to a previously existing layer of polymerized ARTISS, as ARTISS will not adhere to a polymerized layer.

It is recommended that the initial application cover the entire surface area to be treated.

As a guide for surface sealing, 1 ARTISS package of 2 ml (1 ml of fibrin sealant solutionplus1 ml of thrombin solution) will be sufficient, at least, for an area of 10 cm2.

The skin graft should be placed in the wound bed immediately after the application of ARTISS. The surgeon has up to 60 seconds to manipulate and position the graft before polymerization. After the graft or flap has been positioned, keep it in the desired position by gentle compression for at least 3 minutes to ensure that ARTISS adheres properly and that the graft or flap adheres firmly to the underlying tissue.

The amount of ARTISS needed depends on the size of the surface area to be covered. The approximate surface areas covered by each ARTISS package size when applied by spraying are as follows:

To avoid excessive granulation tissue formation and to ensure gradual absorption of the solidified fibrin adhesive, only a thin layer of the mixed fibrin sealant-thrombin solutions should be applied.

ARTISS has not been administered to patients over 65 years in clinical trials.

Pediatric population

Available data are described in section 5.1 of the SmPC but no dosage recommendation can be established.

Administration

For topical use (episiotomy). Do not inject.

Only for subcutaneous use. The use of ARTISS in laparoscopic surgery is not recommended.

To ensure safe and optimal use of ARTISS, it should be sprayed using a pressure regulator device that provides a maximum pressure of up to 2.0 bars (28.5 psi).

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

ARTISS should only be sprayed onto visible application areas.

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

For spraying application, see the Administration section below.

Before administering ARTISS, the area around the wound should be protected/covered sufficiently to prevent any unwanted tissue adhesion.

Special precautions for disposal and other manipulations (final package: PRIMA syringe)

General

• Before administering ARTISS, take care to cover all body parts outside the treated area to prevent any unwanted tissue adhesion.
• To avoid ARTISS adhesion to gloves and surgical instruments, these should be moistened with a sodium chloride solution before contact.
• As a guide for surface sealing, 1 ARTISS package of 2 ml (1 ml of fibrin sealant solutionplus1 ml of thrombin solution) will be sufficient, at least, for an area of 10 cm2.
• The required dose depends on the size of the surface area to be covered.
• DO NOT apply the two components of ARTISS separately. Both components must be applied together.
• DO NOT expose ARTISS to temperatures above 37°C. DO NOT heat in a microwave.
• DO NOT thaw the product by holding it in your hands.
• DO NOT use ARTISS until it has thawed completely and been warmed to 33°C–37°C.
• Remove the protective cap from the syringe only when thawing and warming have been completed. To facilitate the removal of the cap from the syringe, gently rock the cap back and forth and remove the protective cap from the syringe.
• Expel all air from the syringe and then connect the connection nozzle and the application cannula.

Instructions for handling and preparation

The inner pouch and its contents are sterile unless the integrity of the outer package is compromised. Use a sterile technique to 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 maintained at room temperature (not above 25°C) for a maximum of 14days. 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 adhesive using a sterile water bath at a temperature of 33°C‑37°C.

• The water bathmust notexceed 37°C. To monitor the specified temperature range, the water temperature should be controlled 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 water bath. Ensure that the contents of the ready-to-use syringe are completely submerged in the water.

Table 1: 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 inside 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 time. 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: 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 inside both pouches and place it in an incubator outside the sterile field for an adequate period of time (see Table3). After thawing/warming, 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: 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 inside both pouches and thaw it at room temperature outside the sterile field for an adequate period of time (see Table4). Once thawed, to warm the product for use, warm it in the outer pouch in an incubator.After thawing at room temperature, the maximum time the product can be maintained (in both pouches) at room temperature is 14days.

Table 4: Minimum thawing times at room temperature (=TA) outside the sterile field and additional warming times in incubator at 33°C to 37°C

Stability after thawing

Afterthawing and warming(at temperatures between 33°C and 37°C, methods 1, 2, and 3), the chemical and physical stability has been demonstrated for 4hours at a temperature between 33°C and 37°C.

In the case of the productthawedat room temperature in the unopened pouch (method4), the chemical and physical stability has been demonstrated for 14days at temperatures not exceeding 25°C. Warm to a temperature between 33°C and 37°C immediately before use.

From a microbiological point of view, unless the method of opening and thawing excludes the risk of microbial contamination, the product should be used immediately after being warmed between 33°C and 37°C.

Unless used immediately, the necessary conditions and times for 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 adhesive,keep the two components at 33°C-37°C until application.

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

The thawed fibrin sealant 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, DO NOT use ARTISS in any way.

• Remove the syringe from the pouches just before using it.
• Use ARTISS only when it has thawed and warmed completely (liquid consistency).
• Remove the protective cap from the syringe immediately before application.

Administration without spraying with the PRIMA syringe:

For application, the dual-chamber ready-to-use syringe with fibrin sealant solution and thrombin solution should be connected to a connection nozzle and an application cannula, included in the application device. The common plunger of the dual-chamber ready-to-use syringe, included in the application device, ensures that equal volumes of the two components of the tissue adhesive will exit through the connection nozzle into the application cannula, where they will mix before application.

Instructions for use of the PRIMA syringe:

• Expel all air from the syringe before connecting it to any application device.
• Align the connection nozzle and anchor the lateral side of the syringe in the orifice of the anchoring band.

• Connect the nozzles of the dual-chamber ready-to-use syringe to the connection nozzle and ensure that both are securely attached.

• Secure the connection nozzle by fixing the anchoring band to the dual-chamber ready-to-use syringe.
• If the anchoring band breaks, use the connection nozzle included in the package.
• If no spare connection nozzle is available, the system can still be used if the connection is secure and leak-proof.
• DO NOT expel the air remaining in the connection nozzle.

• Connect an application cannula to the connection nozzle.

• DO NOT expel the air remaining in the connection nozzle and application cannula until application begins, as this may obstruct the application cannula.

Administration

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

• Apply the mixed fibrin sealant-thrombin solution to the surface or surfaces of the parts to be sealed by slowly pressing the rear of the common plunger.
• In surgical procedures requiring the use of minimal volumes of fibrin tissue adhesive, it is recommended to expel and discard the first drops of the product.
• After applying ARTISS, wait at least 3minutes for sufficient polymerization.

Nota:If the application of the components of the fibrin tissue adhesive is interrupted, coagula may form in the cannula. In this case, replace the application cannula with a new one immediately before reinitiating application. If the openings of the connection nozzle become obstructed, use the additional connection nozzle provided in the package.

BAXTER also provides other accessories for application that are particularly suitable for, e.g., application in large or hard-to-reach areas. When using these application devices, the Instructions for Use of the devices must be followed strictly.

For further preparation instructions, consult the responsible nurse or doctor.

Application by spraying

The pressure regulator should be used according to the manufacturer's instructions.

When applying ARTISS with a spraying device, ensure that a pressure and distance to the tissue within the recommended intervals by the manufacturer are used as follows:

When spraying ARTISS, the changes in arterial pressure, pulse, oxygen saturation, and CO2at the end of expiration should be monitored to detect possible gas embolism (air or gas) (see sections 4.2 and 4.4).

When using accessory nozzles with this product, the instructions for use of the nozzles should be followed.

Elimination

The elimination of unused medicinal product and all materials that have been in contact with it will be carried out in accordance with local regulations.