Artiss

Package leaflet: Information for the user

ARTISS
Solutions for preparation of tissue glue
Deep-frozen
Human fibrinogen, human thrombin, aprotinin, calcium chloride dihydrate
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet:

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

1. What ARTISS is and what it is used for
What ARTISS is
ARTISS is a two-component fibrin tissue glue containing two of the proteins that form blood clots. These proteins are called fibrinogen and thrombin. When these proteins mix during administration, they form a clot at the site where the surgeon applies them.
ARTISS is supplied as two solutions (fibrin glue protein solution and thrombin solution) which are mixed during application.

What ARTISS is used for
ARTISS is a tissue adhesive.
ARTISS is used to bond soft tissues in plastic and reconstructive surgery and in burn treatment. For example, ARTISS may be used to secure skin grafts or skin flaps to burn wounds or in plastic surgery to adhere skin to underlying tissue. ARTISS can also be used to attach artificial skin to a wound site.
The clot formed by ARTISS is very similar to a natural blood clot. This means it dissolves naturally and leaves no residue. However, aprotinin (a protein that delays clot dissolution) is added to increase the durability of the clot and prevent its premature breakdown.

2. Important information before using ARTISS

Do not use ARTISS:

• If the patient is allergic to the active substances or to any of the other ingredients of this medicine (listed in section 6).
• ARTISS should not be used to treat massive or brisk bleeding.
• ARTISS should not be used as a substitute for skin sutures intended to close a surgical wound.
• ARTISS MUST NOT be injected into blood vessels (veins or arteries) or into tissues. Since ARTISS forms clots at the site of application, injecting ARTISS may cause serious reactions (e.g. vessel occlusion). ARTISS should be applied exclusively to tissue surfaces as a thin layer, only where needed.
• Do not administer ARTISS to patients with known allergy (hypersensitivity) to the active substances, bovine protein, or any other component (see section 6) of ARTISS. This may cause severe allergic reactions. Inform the surgeon or another physician if the patient knows they are allergic to aprotinin or any bovine protein.
• The spray application of ARTISS should not be used in endoscopic procedures. For use in laparoscopy (surgical procedures through body wall openings), see section "Warnings and precautions".

Warnings and precautions

• Discuss the use of ARTISS with your doctor, pharmacist, or nurse before starting treatment.
• During the use of spray devices equipped with pressure regulators for the application of fibrin tissue glues, life-threatening or fatal air and gas embolisms (air or gas entering the bloodstream, potentially leading to serious health risks or death) have been reported. These events appear to be associated with using the spray device at pressures higher than recommended and/or very close to the tissue surface. The risk appears greater when fibrin tissue glues are sprayed with air rather than with CO₂. Therefore, such an event cannot be excluded when spraying ARTISS.
• When applying ARTISS with a spray device, the pressure and spray distance must remain within the range recommended by the device manufacturer. ARTISS must be administered strictly according to instructions and only with devices recommended for use with this product.
• When spraying ARTISS, monitor arterial blood pressure, pulse, arterial oxygen saturation, and end-tidal CO₂ concentration due to the risk of gas embolism.
• Do not use ARTISS with the EasySpray/Spray Set in closed body cavities due to serious safety concerns.
• ARTISS is not recommended for laparoscopic procedures (surgical procedures performed through body wall openings).
• ARTISS should only be applied using devices bearing the CE mark.
• When using auxiliary tips with this product, follow the instructions for use of those tips.
• If the patient has previously received ARTISS or aprotinin, their body may have become sensitized. The patient may be allergic to this product even if no reactions occurred during the first administration. If the patient suspects they received one of these products during a previous surgery, they must inform their doctor.
• If any symptoms of an allergic reaction occur, the doctor will immediately discontinue ARTISS and initiate appropriate treatment.
• ARTISS is not indicated to support haemostasis and tissue bonding when rapid glue setting is required. ARTISS should not be used, in particular, in cardiovascular surgery where glue is intended for vascular anastomoses.
• ARTISS is not indicated for use in neurosurgery or as a sealant for anastomoses of the gastrointestinal tract or vascular anastomoses, as there is no data supporting these indications.
• Before applying ARTISS, surrounding body areas outside the target site must be adequately protected/shielded to prevent unintended tissue adhesion.
• ARTISS is applied as a thin layer. Excessive clot thickness may adversely affect product efficacy and wound healing.
• The physician should not use materials containing oxidized cellulose as carriers, as they may reduce the effectiveness of ARTISS.

For medicines derived from human blood or plasma, specific measures are taken to prevent transmission of infections to patients. These measures include:

• Careful donor selection of blood and plasma to ensure individuals at risk of carrying infections are excluded,
• Testing individual blood samples and pooled plasma for viruses/infections,
• Including manufacturing steps that inactivate or remove viruses during blood or plasma processing.

Despite these measures, when administering medicines derived from human blood or plasma, the possibility of transmitting infection cannot be completely ruled out. This includes unknown or newly emerging viruses and other infectious agents.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, as well as the non-enveloped hepatitis A virus.
The measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be dangerous for pregnant women (fetal infection) and for individuals with weakened immune systems or certain types of anemia (e.g. hereditary spherocytosis or hemolytic anemia).
It is strongly recommended that each time a dose of ARTISS is administered to a patient, the product name and batch number be recorded to maintain traceability of the batches used.

ARTISS and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
ARTISS may be used concurrently with other medicines the patient is taking. No interactions between ARTISS and other medicinal products are known.
Like other similar preparations or thrombin solutions, the product may be inactivated by solutions containing alcohol, iodine, or heavy metals (e.g. disinfectants). Such substances should be thoroughly removed before application of the product.

ARTISS with food and drink
Ask your doctor. The doctor will decide whether the patient may eat and drink before administration of ARTISS.

Pregnancy and breastfeeding
If the patient is pregnant, breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor before using this medicine. The doctor will decide whether ARTISS can be used during pregnancy or breastfeeding.

Driving and using machines
ARTISS has no influence on the ability to drive or operate machinery.

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

3. How to use ARTISS

• ARTISS is used exclusively during surgical procedures. ARTISS may only be administered by experienced surgeons who have been specifically trained in its use.
• The amount of ARTISS used will depend on several factors, including the type of procedure, the size of the tissue surface area to be treated, and the method of application. The surgeon will determine the appropriate quantity.
• During surgery, the surgeon will apply ARTISS to the appropriate tissue surface using the special application device provided. This device ensures simultaneous and equal delivery of both components of the fibrin glue, which is essential for achieving the optimal effect of ARTISS.
• Prior to application of ARTISS, the wound surface should be dried using standard techniques (e.g., gauze pads, sponges, suction devices).
• ARTISS may only be sprayed onto surfaces that are clearly visible.
• It is recommended that the initial application covers the entire intended treatment area.

When applying ARTISS using the spray device, the manufacturer's instructions for pressure and distance from the tissue must be followed, within the ranges specified below:

During spraying of the ARTISS product, monitor changes in arterial pressure, heart rate,
arterial oxygen saturation, and end-tidal CO concentration due to the possibility of
air or gas embolism (see section 2).
Use of a higher than recommended dose of ARTISS
ARTISS is used exclusively during surgical procedures. It is applied by the surgeon, and the amount of ARTISS is also determined by the surgeon.
If there are any questions regarding the use of the medicinal product, please consult a physician or pharmacist.

4. Possible adverse reactions

Like all medicines, this product may cause adverse reactions, although not everyone will experience them.
The table below explains how to interpret the different frequency categories listed in the following section:
Very common: may affect more than 1 in 10 patients
Common: may affect up to 1 in 10 patients
Uncommon: may affect up to 1 in 100 patients
Rare: may affect up to 1 in 1,000 patients
Very rare: may affect up to 1 in 10,000 patients
Not known: frequency cannot be estimated from available data

• There is a small possibility that a patient may experience an allergic reaction to one of the components of ARTISS (see section 6). This is more likely if the patient has previously been treated with ARTISS or aprotinin during a prior surgery. Allergic reactions may be severe, and it is very important to discuss the possibility of such reactions thoroughly with the physician.
• Anaphylactic/anaphylactoid-type reactions may occur; the frequency is not known. Early signs of allergic reactions may include: sudden flushing, drop in blood pressure, increased or decreased heart rate, nausea (feeling sick), urticaria (hives), itching, difficulty breathing.
• The surgical team performing the procedure is aware of the risk of such reactions—if any symptoms are observed, administration of ARTISS will be immediately stopped. Severe symptoms may require emergency interventions. The frequency of allergic reactions is not known.
• Injection of ARTISS into soft tissues may cause local tissue damage. Frequency is not known.
• Injection of ARTISS into blood vessels (veins or arteries) may lead to clot formation (thrombosis). Frequency is not known.
• Since ARTISS is manufactured from plasma derived from human donor blood, the risk of transmitting infectious agents cannot be completely ruled out. However, the manufacturer takes numerous measures to minimize this risk (see section 2).
• Life-threatening or fatal cases of air or gas embolism (air entering the bloodstream, which may lead to serious or life-threatening conditions) have occurred with the use of spray devices employing pressure regulators to administer Baxter fibrin sealants. These events appear to be associated with the use of spray devices at higher than recommended pressures and/or at distances closer than recommended from the tissue surface.

Adverse reactions reported during clinical trials of ARTISS and following post-marketing experience with Baxter fibrin sealants are listed below. The frequencies of adverse reactions provided are based on data from a controlled clinical study involving 138 patients in which ARTISS was used to secure skin grafts over excised burn wounds. None of the adverse reactions observed in the clinical study were classified as severe.
Table 1
Adverse reactions

* The occurrence of air or gas bubbles in the vascular system has been reported when fibrin
adhesives are applied using compressed air or gas devices; this appears to be associated with
improper use of the spray device (e.g., at higher than recommended pressure and/or closer than
recommended distance from the tissue surface).
The following adverse reactions have been reported for other tissue adhesives; their frequency cannot
be determined: allergy, severe allergic reaction, slow heart rate, fast heart rate, low blood pressure,
hemorrhagic effusion, shallow breathing, nausea, urticaria, sudden flushing, impaired wound healing,
swelling, fever, and accumulation of lymph and other body fluids under the skin at the site of
procedure.
Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor,
pharmacist, or nurse.
Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions
of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps increase knowledge about the safety of this medicinal product.

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 frozen state (at temperature ≤ -20°C), under unchanged conditions, until ready for use.
• Store the syringe in its original packaging to protect from light.

Storage after thawing
The product in unopened protective pouches, thawed at room temperature, may be stored for up to 14 days at controlled room temperature (not exceeding 25°C).
After thawing, do not refreeze or place in a refrigerator!
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What ARTISS contains
ARTISS contains two components:
Component 1 = Fibrinogen solution:
The active substances in 1 ml of fibrinogen solution are:
Human fibrinogen, 91 mg/ml derived from human plasma; aprotinin 3000 KIU/ml
The excipients are: human albumin, L-histidine, nicotinamide,
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 derived from human plasma; 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 amounts of 0.6–5 IU/ml.
What ARTISS looks like and contents of the pack
Solutions for preparation of tissue glue.
ARTISS is supplied in a prefilled dual-chamber syringe for single use, with a cap, packed in two bags (outer and inner bag), together with one set containing 2 connectors and 4 application needles.
After thawing, the solutions are colourless to pale yellow and clear to slightly turbid.
ARTISS is available in the following pack sizes containing 1 syringe:

• 2 ml (1 ml human fibrinogen and 1 ml human thrombin)
• 4 ml (2 ml human fibrinogen and 2 ml human thrombin)
• 10 ml (5 ml human fibrinogen and 5 ml human thrombin)

Not all pack sizes may be marketed.
Marketing Authorisation Holder
Baxter Polska Sp. z o.o.
ul. Kruczkowskiego 8
00-380 Warsaw
Poland
Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
A-1221 Vienna
Austria
This medicinal product is authorised for marketing in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
ARTISS in the following countries: Austria, Belgium, Czech Republic, Germany, Spain, Finland, France, Ireland, Italy, Luxembourg, Netherlands, Norway, Poland, United Kingdom (Northern Ireland)
Artiss: Denmark, Sweden

Information intended exclusively for medical professionals:

Effects on fertility, pregnancy, and lactation
The safety of fibrin sealants/hemostatic agents in pregnant or breastfeeding women has not been established in controlled clinical trials. Experimental animal studies are insufficient to determine safety with respect to fertility, embryonic or fetal development, course of pregnancy, and perinatal and postnatal development.
Therefore, the product should be used in pregnant or breastfeeding women only if clearly necessary.
The effect of ARTISS on fertility has not been established.

Dosage and method of administration
ARTISS may only be used in a hospital setting. The ARTISS product may be administered solely by experienced surgeons who have received appropriate training in its use.

Dosage
The volume and frequency of ARTISS application must always be adjusted according to the patient's clinical needs.
The required dose depends on various factors, including but not limited to the type of surgical procedure, size of the area to be sealed, and the chosen method of application, as well as the number of applications.
Application of the product must be individually determined by the treating physician. In clinical trials, individually adjusted doses typically ranged from 0.2 to 12 mL. In certain procedures (e.g., management of extensive burn wounds), larger volumes of the product may be required.

The initial dose applied to a selected anatomical site or target surface should be sufficient to completely cover the intended area of application. If necessary, additional application may be performed on small areas that were not previously covered. However, repeated application onto an already polymerized layer of ARTISS should be avoided, as ARTISS will not adhere to the polymerized layer.

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

As a general guideline for surface sealing, one 2 mL package of ARTISS (i.e., 1 mL of the adhesive protein solution plus 1 mL of thrombin solution) is sufficient to cover a surface area of at least 10 cm².

The skin graft should be immediately placed onto the wound site following ARTISS application. The surgeon has approximately 60 seconds to position and maneuver the graft before polymerization occurs. After positioning the flap or graft, it should be held in place with gentle pressure for at least 3 minutes to ensure proper bonding of ARTISS and secure adherence of the graft or flap to the underlying tissue.

The required amount of ARTISS product depends on the surface area to be covered. The approximate surface area covered by a given package size of ARTISS in a spray application is as follows:

To avoid excessive granulation and ensure gradual absorption of the solidified glue into tissues, only very thin layers of the mixture of fibrin sealant solution and thrombin should be applied.
ARTISS has not been used in clinical trials in individuals over 65 years of age.
Pediatric population
Current data are described in section 5.1 of the Product Characteristics, but dosing recommendations cannot be provided.
Method of administration
Topically (locally). Do not inject.
For subcutaneous administration only. ARTISS is not recommended for use in laparoscopic procedures.
To ensure optimal safety conditions during application of ARTISS, it should be applied using a device equipped with a pressure regulator generating a maximum pressure of 2.0 bar (29.0 psi).
Before applying ARTISS, the wound surface should be dried using standard techniques (e.g., changing compresses, gauze, using suction devices). Compressed air or gas must not be used to dry the surface.
ARTISS may only be sprayed onto visible surfaces.
ARTISS must be reconstituted and administered according to the instructions and using devices recommended for use with this product.
For spray application, see section "Administration" below.
Prior to ARTISS application, care should be taken to ensure that body areas adjacent to the target site are adequately protected/shielded to prevent unwanted tissue adhesion.
Special precautions for removal and preparation of the medicinal product for use
General information

• The inner pouch and its contents are sterile unless the integrity of the outer pouch has been compromised.
• The fibrin sealant solution and thrombin solution should be clear or slightly opalescent.
• Do not use solutions that are cloudy, discolored, contain precipitates, or show other changes in appearance, including a solidified gel consistency after thawing.
• Before applying ARTISS, ensure that all body areas outside the target application site are adequately shielded to prevent unwanted tissue adhesion.

Thawing of the frozen formulation

• DO NOT use the ARTISS medicinal product until it is completely thawed and warmed (liquid to slightly viscous consistency).
• ARTISS must not be exposed to temperatures above 37°C, nor subjected to microwave radiation.
• Do not remove the protective cap from the syringe until thawing and warming are complete and the application tip is ready to be attached.
• To facilitate removal of the protective cap from the syringe, move the protective cap forward and backward, then remove the protective cap from the syringe.

Thaw and warm the filled syringe using one of the following methods:
Option 1: Rapid thawing/heating methods (one-step preparation)
a) Sterile water bath
b) Non-sterile water bath
c) Incubator
Option 2: Thawing at room temperature (not exceeding 25°C), followed by heating in an incubator (possible temporary storage for up to 14 days at temperatures not exceeding 25°C)

1. Rapid thawing/heating methods

The rapid thawing/heating methods are described in Table 2.
Table 2: Rapid thawing/heating methods at 33°C–37°C

Warning: When using a water bath, the temperature must not exceed 37°C.
a) Sterile water bath (recommended method)

• Remove the outer bag and transfer the filled syringe, packed in the inner bag, into a sterile area.
• Remove the filled syringe from the inner bag and place the syringe directly into sterile water heated to 33°C–37°C, ensuring that the syringe is completely submerged in the water (minimum thawing/heating times are given in Table 2).
• To maintain the specified temperature range, monitoring of water temperature with a thermometer and water replacement when necessary is required.

b) Non-sterile water bath

• Place the filled syringe, packed in both bags, into a water bath heated to 33°C–37°C outside the sterile area, ensuring that the bags remain submerged in the water (minimum thawing/heating times are given in Table 2).
• After thawing and heating, remove the bags from the water bath.
• Dry and remove the outer bag, then transfer the filled syringe in the inner bag into the sterile area.

c) Incubator

• Place the filled syringe, packed in both bags, into an incubator outside the sterile area (minimum thawing/heating times are given in Table 2).
• After thawing/heating in the incubator, remove the outer bag and transfer the filled syringe in the inner bag into the sterile area.

2. Thawing at room temperature (not exceeding 25°C), followed by heating

in an incubator

• Thaw the filled syringe, packed in both bags, at room temperature outside the sterile area (minimum thawing times are given in Table 3).
• Heat the filled syringe, packed in both bags, in an incubator at 33°C–37°C outside the sterile area (minimum heating times are given in Table 3).
• After thawing/heating in the incubator, remove the outer bag and transfer the filled syringe in the inner bag into the sterile area.

Table 3: Thawing at room temperature and heating in an incubator

Stability after thawing
After thawing and warming to a temperature of 33°C–37°C (option 1 and 2), the product must be used within
4 hours.
Product thawed at room temperature (option 2) may be stored for up to 14 days
at a temperature not exceeding 25°C, in the original, unopened packaging (both bags).
Re-freezing or placing in a refrigerator after thawing has been initiated is not permitted.
Handling the product after thawing/before administration
Before use, warm the product to a temperature of 33°C–37°C.
To achieve optimal mixing of the two solutions and optimal polymerization of the fibrin glue,
the temperature of both glue components should be maintained at 33°C–37°C until application.
The thawed adhesive protein solution should be a slightly viscous liquid. If the solution appears as a gelled substance, it should be assumed that denaturation has occurred (possibly due to interruption of the cold chain or overheating during warming). In such a case, ARTISS must not be used under any circumstances.
Non-spray application
To apply the glue, connect the dual-chamber ready-to-use syringe filled with the adhesive protein solution and thrombin solution to the connector and application needle provided in the accompanying device kit. The common plunger of the dual-chamber ready-to-use syringe ensures simultaneous delivery of equal volumes of both glue components into the connector, where they are then mixed within the application needle and subsequently applied.
Instructions for use

Safety clip
Dual plunger
Dual-chamber syringe
Connector
Application needle

• Remove all air from the syringe before connecting to the delivery device.
• Attach the connector and clip to the side of the syringe with the slot for the safety clip.
• Connect the outlets of the dual-chamber ready-to-use syringe to the connector, ensuring they are securely attached.
  • Secure the connector by fastening the safety clip to the ready-to-use dual-chamber syringe.
  • If the safety clip breaks, use the spare connector provided in the kit.
  • If no spare connector is available, the kit may still be used, provided care is taken to ensure the connection remains secure and leak-proof.
  • DO NOT remove air remaining in the connector.
• Attach the application needle to the connector.
  • DO NOT remove air from the connector or the application needle before beginning actual glue application, as this may cause needle blockage.

Administration
Before applying ARTISS, the wound surface should be dried using standard techniques (e.g., gauze pads, sponges, suction devices). Compressed air or gas must not be used to dry the surface.

• Apply the mixed adhesive protein–thrombin solution to the target surface or surfaces to be bonded by gently depressing the rear part of the common plunger.
• In surgical procedures requiring minimal volumes of fibrin glue, it is recommended to expel and discard the first few drops of the product.
• After application of ARTISS, wait at least 3 minutes to allow sufficient polymerization.

Note: If application of the fibrin glue components is interrupted, the needle may become blocked immediately. In such a case, the application needle should be replaced with a new one immediately before resuming application. If the connector outlets are blocked, use the spare connector provided in the package.
Application is also possible using other devices supplied by BAXTER, specifically designed for application to large or hard-to-reach surfaces. When using such devices, strictly follow their Instructions for Use.
For further preparation instructions, consult a nurse or physician.
Application of the product using a spray device
The pressure regulator must be used in accordance with the manufacturer's instructions.
When applying ARTISS using a spray device, maintain the pressure and distance from tissue as recommended by the manufacturer, as follows:

Equivalent spraying devices intended for use with the product ARTISS may also be used.
When using other spraying devices, follow the instructions for use provided with the device.
During spraying of ARTISS, monitor arterial pressure, heart rate, arterial oxygen saturation, and
end-tidal CO₂ concentration due to the risk of air or gas embolism (see Summary of Product Characteristics,
sections 4.2 and 4.4).
If auxiliary tips are used with this product, follow the instructions for use of the tips.
Disposal of unused product or waste
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.