Artiss

PACKAGE LEAFLET: INFORMATION FOR THE USER

ARTISS

Tissue Adhesive Solution
Frozen
Human Fibrinogen, Human Thrombin, Aprotinin, Calcium Chloride Dihydrate
Please read this leaflet carefully before using this medicine because it contains
important information for you.
Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
If you experience any side effects, including those not listed in this
leaflet, please contact your doctor or pharmacist. See section 4.
Contents of this leaflet

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

1. What ARTISS is and what it is used for

What ARTISS is
ARTISS is a two-component fibrin glue containing two of the proteins that enable blood coagulation. These proteins are called fibrinogen and thrombin. When these proteins mix during application, they form a clot at the site where the surgeon applies them.
ARTISS is supplied as two solutions (Sealing Protein Solution and Thrombin Solution), which are mixed together at the time of application.

What ARTISS is used for
ARTISS is a tissue adhesive.
ARTISS is used for the adherence of soft tissues in plastic surgery, reconstructive surgery, and burn surgery. For example, ARTISS can be used to glue skin grafts or skin flaps onto burn wounds, or to attach skin to underlying tissues in plastic surgery.
ARTISS may also be used to adhere artificial skin to wounds.
The clot formed by ARTISS closely resembles a natural blood clot. This means it will dissolve naturally without leaving any residue. However, aprotinin (a protein that delays clot breakdown) is added to prolong the clot's durability and prevent its premature degradation.

2. What you should know before using ARTISS

Do not use ARTISS:

• if you are allergic to one of the active substances or to any of the other ingredients of this medicine (listed in section 6)
• ARTISS must not be used in the presence of massive or brisk bleeding.
• ARTISS is not intended to replace skin sutures used to close surgical wounds.
• ARTISS MUST NOT be injected into blood vessels (veins or arteries) or into tissues. Since ARTISS forms a clot at the application site, injecting ARTISS may cause serious reactions (e.g. vascular occlusion). ARTISS must be applied exclusively on tissue surfaces to achieve a thin layer exactly where it is needed.
• You must not be treated with ARTISS if you are allergic (hypersensitive) to the active substances, 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.
• The spray application of ARTISS must not be used in endoscopic procedures. For laparoscopy (minimally invasive surgery), see the section “Warnings and precautions”.

Warnings and precautions

• Talk to your doctor, pharmacist, or nurse before using ARTISS.
• Cases of potentially fatal/fatal air embolism or gaseous embolism (air entering the bloodstream, which can be serious or life-threatening) have occurred with the use of spray devices using pressure regulators for the administration of fibrin glues. This event appears to be related to the use of spray devices at pressures higher than recommended and/or too close to the tissue surface. The risk appears to be greater when fibrin glues are nebulized with air rather than with CO_, and therefore cannot be excluded with ARTISS.
• When applying ARTISS using a spray device, pressure and spray distance must remain within the range recommended by the spray device manufacturer. ARTISS must be administered strictly according to the instructions provided and only with devices recommended for this product.
• When spraying ARTISS, any changes in blood pressure, pulse, oxygen saturation, and end-tidal CO\ concentration must be monitored, as gaseous embolism may occur.
• ARTISS must not be used with Easy Spray / Spray Set systems in closed body cavities due to serious safety concerns.
• ARTISS is not recommended for laparoscopic surgery (minimally invasive surgery).
• ARTISS must be applied only with CE-marked application devices.
• If using accessory tips with this product, follow the instructions for use of the tips.
• If you have previously been treated with ARTISS or aprotinin, your body may have become sensitized. You may be allergic to this product, even if no reaction occurred during the first application. If you think you may have been treated with either of these products during a previous operation, you must inform your doctor.
• If any symptoms of an allergic reaction occur, your doctor will immediately discontinue the use of ARTISS and initiate appropriate treatment.
• ARTISS is not indicated for stopping bleeding or sealing in situations requiring rapid sealing agent coagulation. In particular, in cardiac surgery procedures involving sealing of surgical connections between blood vessels, ARTISS must not be used.
• ARTISS is not indicated for use in neurosurgery or as suture support for gastrointestinal or vascular anastomoses, as there are no data supporting these indications.
• Prior to ARTISS administration, body areas outside the application site must be adequately protected/covered to prevent unwanted tissue adhesions.
• ARTISS should be applied to achieve a thin layer. Excessive clot thickness may negatively affect the product's efficacy and wound healing.
• Your doctor will not use preparations containing oxidized cellulose as a supporting material, as they may reduce the effectiveness of ARTISS.

When medicines are manufactured from human blood or plasma, certain
measures are taken to prevent the transmission of infections to patients. These include:

• careful selection of blood and plasma donors to exclude individuals at risk of carrying infections,
• testing of each donation and plasma pool for signs of viruses/infections,
• inclusion of blood and plasma manufacturing steps that can inactivate or remove viruses.

Nevertheless, when medicines prepared from human blood or plasma
are administered, the possibility of transmitting infections cannot be completely excluded. This
also applies to unknown or emerging viruses or other types of infections.
The measures taken are considered effective against enveloped viruses such as human
immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV),
and against the non-enveloped hepatitis A virus (HAV).
The measures may have limited effectiveness against non-enveloped viruses such as
parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection), and in individuals with weakened immune systems or certain types of anemia (e.g. sickle cell anemia or hemolytic anemia).
It is strongly recommended that, each time you receive an application of ARTISS, the product name and batch number are recorded to allow traceability of the batches used.

Other medicines and ARTISS
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
ARTISS can be used if you are taking other medicinal products. No known interactions exist between ARTISS and other medicinal products.
As with comparable products or thrombin solutions, the product may be inactivated by contact with solutions containing alcohol, iodine, or heavy metals (e.g. antiseptic solutions). Care should be taken to remove such substances as completely as possible before applying the product.

ARTISS with food and drink
Ask your doctor for advice. Your doctor will decide whether you may consume food and drink before the application of ARTISS.

Pregnancy and breastfeeding
If you are pregnant or breastfeeding, if you suspect you may be pregnant, or if you are planning a pregnancy, ask your doctor for advice before taking this medicine.
Your doctor will decide whether you can use ARTISS during pregnancy or breastfeeding.

Driving and using machines
ARTISS does not impair your ability to drive or operate machinery.

ARTISS contains Polysorbate 80
Polysorbate 80 may cause skin allergies (e.g. rash, itching).

3. How to use ARTISS

• ARTISS is applied exclusively during a surgical procedure. The use of ARTISS is restricted to experienced surgeons specialized in the application of ARTISS.
• The amount of ARTISS used depends on several factors, such as the type of surgical procedure, the surface area of tissue to be treated during the procedure, and the method of ARTISS application. The surgeon will determine the appropriate dosage.
• During the procedure, the surgeon will apply ARTISS to the target tissue surface using the dedicated application device provided. This device ensures that equal amounts of both components of the fibrin glue are applied simultaneously. This is important for achieving the optimal effect of ARTISS.
• Prior to applying ARTISS, the wound surface must be dried using standard techniques (e.g., intermittent application of gauze, swabs, or use of suction devices).
• ARTISS should only be sprayed onto visible application areas.
• It is recommended that the initial amount of product applied covers the entire area intended for treatment. When applying ARTISS using a spray device, ensure that the pressure and distance from the tissue are within the ranges recommended by the manufacturer as indicated below:

When ARTISS is sprayed, any changes in arterial pressure, pulse, oxygen saturation, and end-tidal CO₂ concentration should be monitored, as air embolism or gaseous embolism may occur (see paragraph 2).
If you use more ARTISS than you should
ARTISS is applied only during a surgical procedure, and the surgeon is responsible for its application and for determining the dosage of ARTISS to be used.
If you have any doubts about the use of this product, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
The table below explains the meaning of the frequencies listed in the summary that follows:

• There is a small possibility of an allergic reaction to one of the components of ARTISS (see section 6). This is more likely if you have previously been treated with ARTISS or aprotinin during a prior surgical procedure.

Allergic reactions can be severe, and it is very important to discuss this possibility thoroughly with your doctor.

• Anaphylactic or anaphilactoid-type allergic reactions may occur. The frequency of such reactions is unknown. Early symptoms of allergic reactions may include: flushing, drop in blood pressure, increased or decreased pulse rate, nausea (feeling unwell), urticaria, itching, breathing difficulties.
• The surgical team will be aware of the risk of these types of reactions. If symptoms occur, administration of ARTISS will be stopped immediately. Severe symptoms may require emergency treatment. The frequency of allergic reactions is unknown.
• If ARTISS is injected into soft tissues, it may cause local tissue damage. The frequency is unknown.
• If ARTISS is injected into blood vessels (veins or arteries), it may cause blood clots (thrombosis). The frequency is unknown.
• Since ARTISS is derived from plasma obtained from blood donations, the risk of transmission of infections cannot be completely excluded. The manufacturer takes numerous measures to reduce this risk (see section 2).
• Potentially life-threatening or fatal air embolism or gaseous embolism (air entering the bloodstream, which may be serious or life-threatening) has occurred with the use of spray devices using pressure regulators to administer fibrin sealants. This appears to be related to the use of spray devices at pressures higher than recommended and/or close to the tissue surface.

Adverse reactions reported from clinical studies of ARTISS and post-marketing experience with Baxter fibrin sealants are summarised below. The known frequencies of these adverse reactions are based on a controlled clinical study conducted in 138 patients, in which skin grafts were fixed to excised burn wounds using ARTISS. None of the events observed during clinical studies were classified as severe.

The following adverse reactions have been reported for other fibrin glues, although their frequencies cannot be provided: allergy, severe allergic reaction, slowed heartbeat, rapid heartbeat, decreased blood pressure, hematoma, shortness of breath, feeling unwell, urticaria, redness, impaired wound healing, swelling, fever, and accumulation of lymph and other clear bodily fluids under the skin near the surgical site.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You may also report adverse reactions directly through the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. How to store ARTISS

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date stated on the label after “Exp.”.
• Store and transport in a freezer (at temperature  -20°C) continuously until preparation for use.
• Keep the syringe in the original packaging to protect the medicine from light.

Storage after thawing:
Unopened packages, thawed at room temperature, may be stored for up to 14 days at controlled room temperature (not exceeding +25°C).
After thawing, the solutions must not be refrozen or refrigerated!
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What ARTISS contains
ARTISS contains two components:
Component 1 = Sealing protein solution
The active substances in 1 ml of Sealing protein solution are:
Human Fibrinogen, 91 mg/ml produced from plasma of human donors;
Synthetic Aprotinin 3000 KIU/ml.
The excipients are Human Albumin, L-histidine, Niacinamide, Polysorbate 80, Dihydric Sodium Citrate and Water for Injections;
Component 2 = Thrombin solution
The active substances in 1 ml of Thrombin solution are:
Human Thrombin, 4 IU/ml produced from plasma of human donors;
Calcium Chloride Dihydrate, 40 mol/ml.
The excipients are Human Albumin, Sodium Chloride and Water for Injections.

ARTISS contains Human Factor XIII co-purified with Human Fibrinogen in a range of 0.6 – 5 IU/ml.
Description of the appearance of ARTISS and contents of the pack
Tissue adhesive solution
Frozen tissue adhesive solution (1 ml, 2 ml or 5 ml of Sealing Protein Solution and 1 ml, 2 ml or 5 ml of Thrombin Solution in a single-use dual-chamber syringe, in a pack).
Pack size: 1.
Contents of the pack with AST syringe:
1 ml, 2 ml or 5 ml of Sealing Protein Solution and 1 ml, 2 ml or 5 ml of Thrombin Solution in a pre-filled, single-use dual-chamber syringe (polypropylene), closed with a protective cap, packaged in two wrappers, and a kit of accessories comprising a single syringe plunger for the dual-chamber syringe, 2 connector pieces, and 4 application cannulae.
The solution is colourless or pale yellow.
Not all pack sizes may be marketed.
Marketing Authorization Holder and Manufacturer
Holder : Baxter S.p.A. – Via del Serafico, 89 – 00142 Rome, Italy
Manufacturer :
Baxter AG
Industriestraße 67
A-1221 Vienna
Austria
This medicinal product is authorized in the European Economic Area countries
under the following names:
ARTISS in the following countries: Austria, Belgium, Czech Republic, Germany, Greece, Spain,
Finland, France, Ireland, Italy, Luxembourg, Netherlands, Norway, Poland, Portugal, United
Kingdom
Artiss in Denmark, Iceland, Sweden

The following information is intended exclusively for physicians or healthcare professionals:

Fertility, pregnancy and lactation
No controlled clinical studies have been conducted to demonstrate the safety of fibrin sealants/hemostatics for use during pregnancy or breastfeeding. In addition, no animal studies have been performed.
Therefore, the product should be administered to pregnant and breastfeeding women only if clearly necessary.
The effects of ARTISS on fertility have not been established.

Dosage and administration
ARTISS is intended for hospital use only. The use of ARTISS is restricted to surgeons experienced and specialized in the use of ARTISS.

Dosage
The amount of ARTISS to be applied and the frequency of application must always be determined according to the individual patient's clinical needs.
The dose to be administered depends on several variables, including but not limited to, the type of surgical procedure, the size of the area to be treated, the method of application, and the number of applications.
The decision to apply the product must always be made on a case-by-case basis by the treating physician.
In clinical trials, the individual dose range was generally between 0.2 and 12 ml. For certain procedures (e.g., repair of extensive burn areas), larger volumes may be required.

The initial amount of product applied to a specific anatomical site or target area should be sufficient to cover the entire area to be treated. If necessary, additional applications may be performed on small untreated areas. However, reapplication of ARTISS onto a previously polymerized ARTISS layer should be avoided, as ARTISS will not adhere to a polymerized layer.

It is recommended that the initial amount of product applied completely covers the entire area to be treated.

As a general guideline for surface bonding, one 2 ml ARTISS kit (i.e., 1 ml Sealing Protein Solution plus 1 ml Thrombin Solution) is sufficient for an area of at least 10 cm².

The skin graft must be fixed to the wound bed immediately after application of ARTISS. The surgeon has up to 60 seconds to manipulate and position the graft before polymerization occurs. After placement of the skin flap or skin graft, maintain it in the desired position with gentle pressure for at least 3 minutes to ensure proper adhesion of ARTISS and secure attachment of the skin flap or graft to the underlying tissue.

The amount of ARTISS required depends on the size of the surface to be covered. Approximate surface areas covered by each ARTISS kit when applied by spray are:

To avoid excessive granulation tissue formation and ensure gradual absorption of the solidified fibrin glue, apply only a thin layer of the mixed solution of coagulable proteins and thrombin.
ARTISS has not been administered in clinical studies to patients over 65 years of age.
Paediatric population
The currently available data are described in section 5.1 of the Summary of Product Characteristics, but no dosage recommendations can be made.
Method of administration
For epidermal (topical) use. Do not inject.
For subcutaneous use only. ARTISS is not recommended for laparoscopic surgery.
To ensure optimal safety during use, ARTISS must be sprayed using a pressure-regulating device delivering a maximum pressure not exceeding 2.0 bar (28.5 psi).
Before applying ARTISS, the wound surface must be dried using standard techniques (e.g. intermittent application of gauze, swabs, or use of suction devices). Do not use compressed air or gas to dry the area.
ARTISS must be sprayed only onto visible application areas.
ARTISS must be reconstituted and administered according to the instructions provided and only with the devices recommended for this product.
For spray application, refer to the Administration section below.
Before administering ARTISS, ensure that body parts outside the application area are adequately protected/covered to prevent tissue adhesion at unintended sites.
Special precautions for disposal and handling (final container: AST syringe)
General information

• Before administering ARTISS, cover all body parts outside the treatment area to prevent tissue adhesion at unintended sites.
• To prevent ARTISS from adhering to gloves and instruments, moisten them with physiological saline solution before contact.
• As a guideline for bonding surfaces, one 2 ml ARTISS kit (i.e. 1 ml of Sealing Protein Solution plus 1 ml of Thrombin Solution) will be sufficient for an area of at least 10 cm².
• The required dose depends on the size of the surface 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 use a microwave.
• DO NOT thaw the product by holding it in hands.
• DO NOT use ARTISS until it is completely thawed and warmed to 33°C – 37°C.
• Remove the protective cap from the syringe only after thawing and warming are complete.
• Expel all air from the syringe, then attach the connector element and the application cannula.

Instructions for handling and preparation of the product
The inner pouch and its contents are sterile unless the integrity of the outer packaging is compromised. Using aseptic technique, transfer the sterile inner pouch and its contents into the sterile field.
The ready-to-use syringe may be thawed AND warmed using one of the following methods:

1. Rapid thawing/heating (with sterile water bath) – Recommended method

2. Thawing/heating with non-sterile water bath
3. Thawing/heating in incubator
4. The ready-to-use syringe may also be thawed and stored at room temperature (not exceeding 25°C) for up to 14 days. Heating is required before use.

1) Rapid thawing/heating (with sterile water bath) – Recommended method
It is recommended to thaw and heat both components of the sealant using a sterile water bath at a temperature of 33–37°C.

• The water bath must not exceed a temperature of 37°C. To monitor the specified temperature range, check the water temperature with a thermometer and change the water if necessary.
• When using a sterile water bath for thawing and heating, remove the pre-filled syringe from its packaging before placing it into the sterile water bath.

Instructions:
Bring the inner pouch into the sterile area, remove the ready-to-use syringe from the inner pouch, and place it directly into the sterile water bath. Ensure that the contents of the ready-to-use syringe are completely submerged in the water.
Table 1: Minimum thawing and heating times using a sterile water bath

2) Thawing / warming using a non-sterile water bath
Instructions:
Leave the ready-to-use syringe inside both its wrappers and place it in a water bath outside the sterile area for the required time (see Table 2).
Ensure the wrappers remain submerged in water throughout the entire thawing process. After thawing, remove the wrappers from the water bath, dry the outer wrapper, and transfer the inner wrapper with the ready-to-use syringe into the sterile area.
Table 2 - Minimum thawing and warming times using a non-sterile water bath

3) Thawing / warming in an incubator
Instructions:
Leave the ready-to-use syringe inside both its packaging layers and place it in the
incubator outside the sterile area for the appropriate period of time (see Table
3). After thawing / warming, remove the packaging from the incubator,
discard the outer wrapper, and transfer the inner wrapper with the ready-to-use syringe
into the sterile area.
Table 3: Minimum thawing and warming times in an incubator

4) Thawing at room temperature (not exceeding 25°C) BEFORE heating:
Instructions:
Leave the ready-to-use syringe inside both its packaging layers and thaw at room temperature outside the sterile area for the appropriate period of time (see Table 4). Once thawed, to warm the product for use, heat it in the outer packaging in an incubator. After thawing at room temperature, the maximum storage time of the product (in both its packaging layers) at room temperature is 14 days.
Table 4: Minimum thawing times at room temperature (= RT) outside the sterile area and additional warming in an incubator at 33°C to 37°C.

Stability after thawing
After thawing and 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 4 hours between 33°C
and 37°C.
For the product thawed at room temperature in the unopened packaging (method 4), the chemical and physical stability of the product has been demonstrated for 14 days at temperatures not
exceeding 25°C. Warm to temperatures between 33°C and 37°C immediately before use.
From a microbiological standpoint, unless the method of opening/thawing precludes the risk of microbial contamination, the product should be used immediately after warming between 33°C and 37°C.
If not used immediately, the times and conditions of storage during use are the responsibility of the user.
Do not refreeze or refrigerate once thawing has begun.

Handling after thawing / prior to application
To achieve optimal mixing of the two solutions and optimal solidification of the fibrin-based sealant, maintain both components of the sealant at 33°C – 37°C until application.
The sealant protein and thrombin solutions should be clear or slightly opalescent. Do not use turbid solutions or those containing deposits. Before use, visually inspect the thawed product for particles, discoloration, or other changes in appearance. If any of the above conditions occur, discard the solutions.
The thawed, sealed protein solution should be liquid but slightly viscous. If the solution has the consistency of a solidified gel, it should be assumed denatured (likely due to a break in the cold chain or overheating during warming). In this case, under no circumstances should ARTISS be used.

• Remove the syringe from its packaging immediately before use.
• Use ARTISS only when fully thawed and warmed (liquid consistency).
• Remove the protective cap from the syringe immediately before application.

Administration without spray:
For application, connect the ready-to-use dual-chamber syringe containing the sealant protein solution and the thrombin solution to a connector piece and an application cannula – both provided in the kit with the application devices. The common plunger of the ready-to-use dual-chamber syringe, also included in the kit, ensures that equal volumes of the two sealant components are delivered through the connector piece into the application cannula, where they are mixed and then applied.
Instructions for use:

• Expel all air from the syringe before connecting any application device.
• Align the connector piece and attach it to the side of the syringe with the tab hole.
• Connect the nozzles of the ready-to-use dual-chamber syringe to the connector piece, ensuring they are securely fixed.
  • Secure the connector piece by fastening the tab to the ready-to-use dual-chamber syringe.
  • If the tab tears, use the spare connector piece provided in the kit.
  • If no spare is available, the system may still be used provided care is taken to ensure a secure, leak-proof connection.
  • DO NOT expel the air remaining inside the connector piece.
• Insert an application cannula into the connector piece.
  • DO NOT expel the air remaining inside the connector piece and the application cannula until actual application begins, as this may clog the cannula.

Administration
Before applying ARTISS, the wound surface must be dried using standard techniques (e.g., intermittent application of swabs or sponges, use of suction devices). Do not use pressurized air or gas to dry the site.

• Apply the mixed sealant solution (protein-thrombin) to the receiving surface or to the surfaces of the parts to be bonded by slowly pressing on the back of the common plunger.
• In surgical procedures requiring minimal volumes of fibrin-based sealant, it is recommended to expel and discard the first drops of the product.
• After applying ARTISS, wait at least 3 minutes to achieve sufficient polymerization.

Note:
If the application of the fibrin-based sealant components is interrupted, blockages may occur in the application cannula. In this case, replace the application cannula with a new one immediately before resuming application. If the openings of the connector piece are blocked, use the spare connector piece provided in the package.
Application is also possible with other accessories supplied by BAXTER that are particularly suitable, e.g., for application in extensive or hard-to-reach areas. When using these application devices, strictly follow the instructions for use provided with the devices.
For further preparation instructions, please consult the responsible nurse or physician.

Spray application
The pressure regulator must be used according to the manufacturer's instructions.
When applying ARTISS using a spray device, ensure that the pressure and distance from the tissue are within the ranges recommended by the manufacturer as specified below:

When ARTISS is sprayed, arterial pressure, pulse, oxygen saturation, and end-tidal CO concentration should be monitored for possible air embolism or gaseous embolism (see
sections 4.2 and 4.4 of the Summary of Product Characteristics).
When using accessory tips with this product, the instructions for use of the tips must be followed.
Disposal
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.

PACKAGE LEAFLET: INFORMATION FOR THE USER

ARTISS

Tissue adhesive solution
Frozen
Human fibrinogen, Human thrombin, Aprotinin, Calcium chloride dihydrate
Please read this leaflet carefully before using this medicine because it contains
important information for you.
Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
If you experience any side effects, including those not listed in this
leaflet, tell your doctor or pharmacist. See section 4.
Contents of this leaflet

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

1. What ARTISS is and what it is used for

What ARTISS is
ARTISS is a two-component fibrin glue containing two of the proteins responsible for blood
coagulation. These proteins are called fibrinogen and thrombin. When these proteins mix during
application, they form a clot at the site where the surgeon applies them.
ARTISS is supplied as two separate solutions (Sealing Protein Solution and Thrombin Solution),
which are mixed together at the time of application.

What ARTISS is used for
ARTISS is a tissue adhesive.
ARTISS is used to adhere soft tissues in plastic surgery, reconstructive surgery, and burn surgery.
For example, ARTISS can be used to glue skin grafts or skin flaps onto burn wounds, or to attach skin to underlying tissues in plastic surgery.
ARTISS may also be used to adhere artificial skin to wounds.
The clot formed by ARTISS closely resembles a natural blood clot. This means it will dissolve naturally without leaving residues. However, aprotinin (a protein that delays clot breakdown) is added to prolong the clot's durability and prevent premature degradation.

2. What you need to know before using ARTISS

Do not use ARTISS:

• if you are allergic to one of the active substances or to any of the other components of this medicinal product (listed in section 6)
• ARTISS must not be used in the presence of massive or brisk bleeding.
• ARTISS is not indicated to replace cutaneous sutures used to close surgical wounds.
• ARTISS MUST NOT be injected into blood vessels (veins or arteries) or into tissues. Since ARTISS forms a clot at the site of application, injecting ARTISS may cause serious reactions (e.g. vascular occlusion). ARTISS must be applied exclusively on the surface of tissues to achieve a thin layer exactly where it is needed.
• You must not be treated with ARTISS if you are allergic (hypersensitive) to the active substances, bovine proteins, or to 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 to any bovine protein.
• The spray application of ARTISS must not be used in endoscopic procedures. For laparoscopy (minimally invasive surgery), see the section “Warnings and precautions”.

Warnings and precautions

• Talk to your doctor, pharmacist, or nurse before using ARTISS.
• Cases of potentially fatal/fatal air embolism or gaseous embolism (air entering the bloodstream, which can be serious or life-threatening) have occurred with the use of spray devices using pressure regulators for the administration of fibrin glues. This event appears to be related to the use of spray devices at pressures higher than recommended and/or too close to the tissue surface. The risk appears to be greater when fibrin glues are nebulized with air rather than with CO**, and therefore cannot be excluded with ARTISS.
• When applying ARTISS using a spray device, the pressure and spray distance must be within the range recommended by the spray device manufacturer. ARTISS must be administered strictly according to the instructions provided and only with devices recommended for this product.
• When spraying ARTISS, any changes in blood pressure, pulse, oxygen saturation, and end-tidal CO* concentration must be monitored, as gaseous embolism may occur.
• ARTISS must not be used with Easy Spray / Spray Set systems in closed body cavities due to serious safety concerns.
• ARTISS is not recommended for laparoscopic surgery (minimally invasive surgery).
• ARTISS must be applied only with CE-marked application devices.
• If accessory tips are used with this product, follow the instructions for use of the tips.
• If you have previously been treated with ARTISS or aprotinin, your body may have become sensitized. You may be allergic to this product, even if no reaction occurred during the first application. If you think you may have been treated with either of these products during a previous operation, you must inform your doctor.
• If any symptoms of an allergic reaction occur, your doctor will immediately discontinue the use of ARTISS and initiate appropriate treatment.
• ARTISS is not indicated for stopping bleeding and sealing in situations where rapid coagulation of the sealant is required. In particular, in cardiac surgery procedures where sealing of surgical connections between blood vessels is expected, ARTISS must not be used.
• ARTISS is not indicated for use in neurosurgery or as a suture support for gastrointestinal anastomoses or vascular anastomoses, as there are no data supporting these indications.
• Prior to administration of ARTISS, areas of the body outside the application site must be adequately protected/covered to prevent unwanted tissue adhesions.
• ARTISS should be applied to form a thin layer. Excessive thickness of the clot may negatively affect the product's efficacy and the wound healing process.
• Your doctor will not use preparations containing oxidized cellulose as a supporting material, as they may reduce the effectiveness of ARTISS.

When medicines are manufactured from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These include:

• careful selection of blood and plasma donors to ensure exclusion of those at risk of carrying infections,
• testing of each donation and plasma pool for signs of viruses/infections,
• inclusion of blood or plasma processing steps that can inactivate or remove viruses.

Nevertheless, when medicines prepared from human blood or plasma are administered, the possibility of transmitting infections cannot be completely excluded. This also applies to unknown or emerging viruses or other types of infections.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), and against the non-enveloped hepatitis A virus (HAV).
The measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in individuals with weakened immune systems or certain types of anemia (e.g. sickle cell anemia or hemolytic anemia).
It is strongly recommended that, each time you receive an application of ARTISS, the name and batch number of the product be recorded, in order to track the batches used.

Other medicines and ARTISS
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
ARTISS can be used if you are taking other medicinal products. There are no known interactions between ARTISS and other medicinal products.
As with comparable products or thrombin solutions, the product may be destroyed by contact with solutions containing alcohol, iodine, or heavy metals (e.g. antiseptic solutions). Care should be taken to remove such substances as completely as possible before applying the product.

ARTISS with food and drink
Ask your doctor for advice. Your doctor will decide whether you may consume food and drink before the application of ARTISS.

Pregnancy and breastfeeding
If you are pregnant or breastfeeding, if you suspect you may be pregnant, or if you are planning to become pregnant, ask your doctor for advice before taking this medicine.
Your doctor will decide whether you can use ARTISS during pregnancy or breastfeeding.

Driving and use of machinery
ARTISS does not impair your ability to drive or use machinery.

ARTISS contains Polysorbate 80
Polysorbate 80 may cause skin allergies (e.g. rash, itching).

3. How to use ARTISS

• ARTISS is applied exclusively during a surgical procedure. The use of ARTISS is restricted to experienced surgeons specialized in the use of ARTISS.
• The amount of ARTISS used depends on several factors, such as the type of surgical procedure, the surface area of tissue to be treated during the procedure, and the method of application of ARTISS. The surgeon will determine the appropriate dosage.
• During the procedure, the surgeon will apply ARTISS to the target tissue surface using the dedicated application device provided. This device ensures that equal amounts of both components of fibrin glue are applied simultaneously. This is important for achieving the optimal effect of ARTISS.
• Prior to applying ARTISS, the wound surface must be dried using standard techniques (e.g., intermittent application of gauze, swabs, or use of suction devices).
• ARTISS should only be sprayed onto visible application areas.
• It is recommended that the initial amount of product applied covers the entire area intended for treatment. When applying ARTISS using a spray device, ensure that the pressure and distance from the tissue are within the ranges recommended by the manufacturer as indicated below:

When ARTISS is sprayed, any changes in arterial pressure, pulse, oxygen saturation, and end-tidal CO concentration should be monitored, as air embolism or gas embolism may occur (see section 2).
If you use more ARTISS than you should
ARTISS is applied only during a surgical procedure, and it is the surgeon who applies it and determines the dosage of ARTISS to be used.
If you have any doubts about the use of this product, ask your doctor or pharmacist for advice.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
The table below explains the meaning of the frequency categories listed in the table provided below:

• There is a small possibility of an allergic reaction to one of the components of ARTISS (see section 6). This is more likely if you have previously been treated with ARTISS or aprotinin during a prior surgical procedure. Allergic reactions can be severe, and it is very important to discuss this possibility thoroughly with your doctor.
• Anaphylactic or anaphylactoid allergic reactions may occur. The frequency of such reactions is unknown. Early symptoms of allergic reactions may include: flushing, drop in blood pressure, increased or decreased pulse rate, nausea (feeling unwell), urticaria, itching, breathing difficulties.
• The surgical team will be aware of the risk of such reactions. If symptoms occur, administration of ARTISS will be stopped immediately. Severe symptoms may require emergency treatment. The frequency of allergic reactions is unknown.
• If ARTISS is injected into soft tissues, it may cause local tissue damage. The frequency is unknown.
• If ARTISS is injected into blood vessels (veins or arteries), it may cause clot formation (thrombosis). The frequency is unknown.
• Since ARTISS is made from plasma obtained from blood donations, the risk of transmitting infections cannot be completely excluded. The manufacturer takes numerous measures to reduce this risk (see section 2).
• Potentially fatal/fatal air embolism or gaseous embolism (air entering the bloodstream, which may be serious or life-threatening) has occurred with the use of spray devices using pressure regulators to administer fibrin sealants. This appears to be related to the use of spray devices at pressures higher than recommended and/or close to the tissue surface.

Adverse reactions reported from ARTISS clinical studies and post-marketing experience with Baxter fibrin sealants are summarized below. The known frequencies of these adverse reactions are based on a controlled clinical study conducted in 138 patients, in which skin grafts were fixed onto excised burn wounds using ARTISS.
None of the events observed during clinical studies were classified as severe.

The following adverse reactions have been reported for other fibrin glues, the frequencies of which cannot be provided: allergy, severe allergic reaction, slowed heartbeat, accelerated heartbeat, decreased blood pressure, hematoma, shortness of breath, feeling unwell, urticaria, redness, impaired wound healing, swelling, fever, and accumulation of lymph and other clear bodily fluids under the skin near the surgical site.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You may also report adverse reactions directly through the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. How to store ARTISS

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date stated on the label after “Exp.”.
• Store and transport in a freezer (at a temperature  -20°C) continuously until preparation for use.
• Keep the syringe in the original packaging to protect the medicine from light.

Storage after thawing:
Unopened packages, once thawed at room temperature, may be stored for up to 14 days at controlled room temperature (not exceeding +25°C).
After thawing, the solutions must not be refrozen or refrigerated!
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What ARTISS contains
ARTISS contains two components:
Component 1 = Sealing protein solution
The active substances in 1 ml of Sealing protein solution are:
Human Fibrinogen, 91 mg/ml produced from plasma of human donors;
Synthetic Aprotinin, 3000 KIU/ml.
The excipients are Human Albumin, L-histidine, Niacinamide, Polysorbate 80, Disodium citrate dihydrate and Water for injections;
Component 2 = Thrombin solution
The active substances in 1 ml of Thrombin solution are:
Human Thrombin, 4 IU/ml produced from plasma of human donors;
Calcium chloride dihydrate, 40 \μmol/ml.
The excipients are Human Albumin, Sodium chloride and Water for injections.

ARTISS contains Human Factor XIII co-purified with Human Fibrinogen in a range of 0.6 – 5 IU/ml.
Description of the appearance of ARTISS and contents of the pack
Solution for tissue adhesive
Frozen solution for tissue adhesive (1 ml, 2 ml or 5 ml of Sealing Protein Solution and 1 ml, 2 ml or 5 ml of Thrombin Solution in a single-use dual-chamber syringe, in a pack).
Pack size: 1.
Contents of the pack with PRIMA syringe:
1 ml, 2 ml or 5 ml of sealing protein solution and 1 ml, 2 ml or 5 ml of thrombin solution in a prefilled, single-use dual-chamber syringe (polypropylene) closed with a protective cap, packaged in two wrappers, and a kit of instruments containing 2 connector pieces and 4 application cannulae.
The solution is colourless or pale yellow.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Baxter S.p.A. – Via del Serafico, 89 – 00142 Rome, Italy
Manufacturer:
Baxter AG
Industriestraße 67
A-1221 Vienna
Austria
This medicinal product is authorised in the European Economic Area Member States
under the following names:
ARTISS in the following countries: Austria, Belgium, Czech Republic, Germany, Greece, Spain, Finland, France, Ireland, Italy, Luxembourg, Netherlands, Norway, Poland, Portugal, United Kingdom
Artiss in Denmark, Iceland, Sweden

The following information is intended exclusively for physicians or healthcare professionals:

Fertility, pregnancy and lactation
No controlled clinical studies have been conducted to demonstrate the safety of fibrin adhesives/hemostatics for use during pregnancy or breastfeeding. In addition, no animal studies have been performed.
Therefore, the product should be administered to pregnant women and those who are breastfeeding only if clearly necessary.
The effects of ARTISS on fertility have not been established.

Posology and method of administration
ARTISS is intended for hospital use only. The use of ARTISS is restricted to experienced surgeons specialized in its application.

Posology
The amount of ARTISS to be applied and the frequency of application must always be determined according to the individual patient's clinical needs.
The dose required depends on several variables, including but not limited to, the type of surgical procedure, the size of the area to be treated, the method of application, and the number of applications.
The decision to apply the product must always be made on a case-by-case basis by the treating physician.
In clinical trials, the individual dose range was generally between 0.2 and 12 ml. For certain procedures (e.g., repair of extensive burn areas), larger volumes may be required.

The initial amount of product applied to a specific anatomical site or target area must be sufficient to cover the entire area intended for treatment. If necessary, reapplication may be performed on small untreated areas. However, reapplication of ARTISS onto a previously polymerized ARTISS layer should be avoided, as ARTISS will not adhere to a polymerized layer.
It is recommended that the initial amount of product applied adequately covers the entire area intended for treatment.

As a general guideline for tissue bonding, one 2 ml package of ARTISS (i.e., 1 ml of Sealing Protein Solution plus 1 ml of Thrombin Solution) is sufficient for an area of at least 10 cm².

The skin graft must be placed onto the wound bed immediately after ARTISS application. The surgeon has up to 60 seconds to manipulate and position the graft before polymerization occurs. After placement of the skin flap or skin graft, maintain it in the desired position with gentle pressure for at least 3 minutes to ensure proper adhesion of ARTISS and secure attachment of the skin flap or graft to the underlying tissue.

The amount of ARTISS required depends on the size of the surface to be covered. Approximate surface areas covered by each ARTISS package when applied by spray are:

To prevent excessive granulation tissue formation and ensure gradual absorption of the solidified fibrin glue, apply only a thin layer of the mixed solution of coagulable proteins and thrombin.
ARTISS has not been administered in clinical studies to patients over 65 years of age.

Pediatric population
The currently available data are described in section 5.1 of the Summary of Product Characteristics; however, no dosage recommendation can be made.

Method of administration
For epicutaneous (topical) use only. Do not inject.
For subcutaneous use only. ARTISS is not recommended for laparoscopic surgery.

To ensure optimal safety during ARTISS application, it must be sprayed using a pressure-regulating device delivering a maximum pressure not exceeding 2.0 bar (28.5 psi).

Prior to ARTISS application, the wound surface must be dried using standard techniques (e.g., intermittent application of gauzes, swabs, or use of suction devices). Do not use compressed air or gas to dry the area.

ARTISS must be sprayed only onto visible application areas.

ARTISS must be reconstituted and administered according to the instructions provided and only with the devices recommended for this product.

For spray application, refer to the Administration section below.

Before administering ARTISS, ensure that body parts outside the application area are adequately protected/covered to prevent tissue adhesion at unintended sites.

Special precautions for disposal and handling ( final container: syringe PRIMA)
General precautions

• Before administering ARTISS, cover all body parts outside the treatment area to prevent tissue adhesion at unintended sites.
• To prevent ARTISS from adhering to gloves and instruments, moisten them with physiological saline solution prior to contact.
• As a general guideline for bonding surfaces, one 2 ml ARTISS kit (i.e., 1 ml Sealing Protein Solution plus 1 ml Thrombin Solution) is sufficient for an area of at least 10 cm².
• The required dose depends on the size of the surface to be covered.
• DO NOT apply the two components of ARTISS separately. Both components must be applied simultaneously.
• DO NOT expose ARTISS to temperatures above 37°C. DO NOT use a microwave.
• DO NOT thaw the product by holding it in hands.
• DO NOT use ARTISS until it is completely thawed and warmed to 33°C–37°C.
• Remove the protective cap from the syringe only after completion of thawing and warming. To facilitate cap removal, shake the cap back and forth, then pull the protective cap off the syringe.
• Expel all air from the syringe, then attach the connector element and the application cannula.

Instructions for Handling and Preparation of the Product
The inner pouch and its contents are sterile unless the integrity of the outer packaging is compromised. Using aseptic technique, transfer the sterile inner pouch and its contents into the sterile field.

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

1. Rapid thawing/warming (using sterile water bath) – Recommended method
2. Thawing/warming using non-sterile water bath
3. Thawing/warming in an incubator
4. The ready-to-use syringe may also be thawed and maintained at room temperature (not exceeding 25°C) for up to 14 days. Warming is required prior to use.

1) Rapid thawing/warming (using sterile water bath) – Recommended method
It is recommended to thaw and warm the two components of the sealant using a sterile water bath at a temperature of 33–37°C.

• The water bath must not exceed a temperature of 37°C. To monitor the specified temperature range, check the water temperature with a thermometer and change the water if necessary.
• When using a sterile water bath for thawing and warming, remove the pre-filled syringe from its pouch before placing it into the sterile water bath.

Instructions:
Bring the inner pouch into the sterile area, remove the ready-to-use syringe from the inner pouch, and place it directly into the sterile water bath. Ensure that the contents of the ready-to-use syringe are completely immersed in the water.

Table 1: Minimum thawing and warming times using sterile water bath

2) Thawing / warming using a non-sterile water bath
Instructions:
Leave the ready-to-use syringe inside both wrappers and place it in a
water bath outside the sterile area for the required time (see Table 2).
Ensure that the wrappers remain submerged in water throughout the
thawing period. After thawing, remove the wrappers from the water bath, dry
the outer wrapper, and transfer the inner wrapper containing the ready-to-use syringe into the sterile area.
Table 2: Minimum thawing and warming times using a non-sterile water bath

3) Thawing / warming in incubator
Instructions:
Leave the ready-to-use syringe inside both its wrappers and place it in the incubator outside the sterile area for the appropriate period of time (see Table 3). After thawing / warming, remove the wrappers from the incubator, discard the outer wrapper, and bring the inner wrapper with the ready-to-use syringe into the sterile area.
Table 3: Minimum thawing and warming times in incubator

4) Thawing at room temperature (not exceeding 25°C) PRIOR to
warming:
Instructions:
Leave the ready-to-use syringe inside both its packaging layers and thaw at room temperature outside the sterile area for the appropriate period of time (see Table 4). Once thawed, to warm the product for use, warm it in the outer packaging layer in an incubator. After thawing at room temperature, the maximum storage time of the product (in both packaging layers) at room temperature is 14 days.
Table 4: Minimum thawing times at room temperature (= RT) outside the sterile area and additional warming in an incubator from 33°C to 37°C.

Stability after thawing
After thawing and 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 4 hours between 33°C and 37°C.
For the product thawed at room temperature in the unopened packaging (method 4), chemical and physical stability has been demonstrated for 14 days at temperatures not exceeding 25°C. Warm to temperatures between 33°C and 37°C immediately before use.
From a microbiological standpoint, unless the method of opening/thawing excludes the risk of microbial contamination, the product must be used immediately after warming to 33°C–37°C.
If not used immediately, the times and conditions of storage during use are the responsibility of the user.
Do not refreeze 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-based sealant, keep both components of the sealant at 33°C–37°C until application.
The sealant protein and thrombin solutions should be clear or slightly opalescent. Do not use cloudy solutions or those containing deposits. Before use, visually inspect the thawed product for particles, discoloration, or other changes in appearance. If any of the above conditions occur, discard the solutions.
The thawed, sealed protein solution should be liquid but slightly viscous. If the solution has a gel-like consistency, it should be assumed denatured (likely due to a break in the cold chain or overheating during warming). In this case, under no circumstances should ARTISS be used.

• Remove the syringe from its packaging immediately before use.
• Use ARTISS only when fully thawed and warmed (liquid consistency).
• Remove the protective cap from the syringe immediately before application. For the PRIMA syringe: to facilitate removal of the cap, gently shake it back and forth, then pull the protective cap off the syringe.

Administration without spray using the PRIMA syringe:
For application, connect the ready-to-use dual-chamber syringe containing the sealant protein solution and thrombin solution to a junction piece and an application cannula—both provided in the application device kit. The common plunger of the ready-to-use dual-chamber syringe ensures equal volumes of both sealant components are delivered through the junction piece into the application cannula, where they are mixed and then applied.

Instructions for use of the PRIMA syringe:

• Expel all air from the syringe before connecting any application device.
• Align the junction piece and secure it to the side of the syringe with the tab.
• Connect the nozzles of the ready-to-use dual-chamber syringe to the junction piece, ensuring they are firmly attached.
  • Secure the junction piece by fastening the tab to the ready-to-use dual-chamber syringe.
  • If the tab breaks, use the spare junction piece provided in the kit.
  • If no spare is available, the system may still be used provided care is taken to ensure a secure, leak-proof connection.
  • DO NOT expel the air remaining inside the junction piece.
• Insert an application cannula into the junction piece.
  • DO NOT expel the air remaining inside the junction piece and the application cannula until the actual application begins, as this may clog the cannula.

Administration
Before applying ARTISS, the wound surface must be dried using standard techniques (e.g., intermittent application of swabs or sponges, use of suction devices). Do not use air or pressurized gas to dry the site.

• Apply the mixed protein-thrombin sealant solution to the receiving surface or to the surfaces of the parts to be bonded by slowly pressing on the back of the common plunger.
• In surgical procedures requiring minimal volumes of fibrin-based sealant, it is recommended to expel and discard the first drops of product.
• After applying ARTISS, wait at least 3 minutes to achieve sufficient polymerization.

Note:
If application of the fibrin-based sealant components is interrupted, blockages may occur in the application cannula. In this case, immediately replace the application cannula with a new one before resuming application. If the openings of the junction piece are blocked, use the spare junction piece provided in the package.
Application is also possible with other accessories supplied by BAXTER that are particularly suitable, e.g., for application over large or hard-to-reach areas. When using these application devices, strictly follow the manufacturer’s instructions for use.
For further instructions regarding preparation, please consult the responsible nurse or physician.

Spray application
The pressure regulator must be used according to the manufacturer's instructions.
When applying ARTISS using a spray device, ensure that the pressure and distance from the tissue are within the ranges recommended by the manufacturer as specified below:

When spraying ARTISS, any changes in arterial pressure, pulse, oxygen saturation, and CO concentration should be monitored, as air embolism or gaseous embolism may occur (see
sections 4.2 and 4.4 of the Summary of Product Characteristics).
When using accessory tips with this product, the instructions for use of the tips must be followed.
Disposal
Unused medicine and waste materials related to this medicine must be disposed of in accordance with local regulations.