Artiss solutions for tissue adhesive, ultrafrozen: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

ARTISS

Solutions for tissue adhesive

Ultra-frozen

Human fibrinogen, human thrombin, aprotinin, calcium chloride dihydrate

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

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

Leaflet contents:

What ARTISS is and what it is used for
What you need to know before using ARTISS
How to use ARTISS
Possible side effects
How to store ARTISS
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 sealant containing two of the proteins involved in blood coagulation. 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 supplied as two solutions (sealing protein solution and thrombin solution), which are mixed when applied.

What Artiss is used for

ARTISS is a tissue adhesive.

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

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

The clot formed by ARTISS is very similar to the naturally occurring clot.

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

2. What you need to know before using Artiss

Do not use ARTISS:

If you are allergic to the active substances or to any of the other components of this medicine (listed in section 6).
ARTISS must not be used in cases of massive or rapid bleeding.
ARTISS is not indicated to replace skin sutures used to close a surgical wound.
ARTISS MUST NOT be injected into blood vessels (veins or arteries) or into tissues. Since ARTISS forms a clot upon application, injecting ARTISS may cause serious reactions (e.g., occlusion of blood vessels). ARTISS should only be applied on tissue surfaces as a thin layer where needed.
Do not receive 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 to any bovine proteins.

ARTISS must not be applied by spraying during endoscopic procedures. For laparoscopic procedures (minimally invasive surgery), see section "Warnings and precautions".

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Artiss.
Cases of gaseous (air or gas) embolism (introduction of air into the bloodstream, which may be fatal or life-threatening) have occurred due to the use of spray devices with pressure regulators to apply fibrin tissue adhesives. These cases appear to be related to the use of spray equipment at pressures higher than recommended and/or at very close distances to the tissue surface. The risk appears greater when fibrin tissue adhesives are sprayed with air compared to CO₂; therefore, such risks cannot be excluded with ARTISS.
When applying ARTISS with a spray device, ensure that both spray pressure and distance are within the range recommended by the manufacturer. ARTISS must be administered exactly as specified in the instructions and only with equipment recommended for this product.
Whenever ARTISS is sprayed, changes in blood pressure, pulse, oxygen saturation, and end-tidal CO₂ levels should be monitored to detect possible gaseous embolism.
ARTISS must not be used with the Easy Spray/Spray Set system in confined anatomical spaces due to serious safety concerns.
Artiss is not recommended for laparoscopic surgery (minimally invasive surgery).
ARTISS should only be applied using CE-marked equipment.
If accessory nozzles are used with this product, follow the instructions for use of the nozzles.
If you have ever received ARTISS or aprotinina, your body may have developed sensitivity. You may become allergic to this material even if you had no reaction during the first application. Inform your doctor if you think you have previously received any of these products during a prior surgery.
If there are any signs of an allergic reaction, your doctor will immediately stop the administration of ARTISS and provide appropriate treatment.
Artiss is not indicated to stop bleeding or for sealing in situations requiring rapid sealant coagulation. In particular, Artiss should not be used in cardiac surgery procedures where the goal is sealing of surgical vascular connections.
ARTISS is not indicated for use in neurosurgery or as support for sutures in gastrointestinal or vascular anastomoses, as there are no available data supporting these indications.
Prior to ARTISS administration, areas of the body outside the application site must be adequately protected/covered to prevent 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 oxy-cellulose as a carrier material, as they may reduce the efficacy of Artiss.

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

careful selection of donors to exclude those at risk of carrying infectious diseases,
testing for specific markers of infection in individual donations and plasma pools,
and inclusion of manufacturing steps designed to inactivate and/or remove viruses.

Despite these measures, the possibility of transmitting infectious agents cannot be completely ruled out when administering medicines derived from human blood or plasma. This also applies to emerging or unknown viruses and other types of infections. These measures are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, as well as against non-enveloped hepatitis A virus.

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 in 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 medicine and the batch number be recorded to maintain traceability of the batches used.

Use of ARTISS with other medicines

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines.

ARTISS may be used simultaneously with other medicines. No interactions between ARTISS and other medicines are known. As with similar products or thrombin solutions, the product may become denatured if exposed to 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.

Use of ARTISS with food and drink

Ask your doctor. Your doctor will decide whether you may eat or drink before ARTISS is administered.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medicine. Your doctor will decide whether ARTISS can be used during pregnancy and breastfeeding.

Driving and using machines

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

3. How to use ARTISS

ARTISS must only be administered during surgical intervention. The use of ARTISS is
limited to experienced surgeons who have been properly trained in the use of
ARTISS.
The amount of ARTISS to be applied depends on several factors, such as the type of
surgery, the size of the tissue surface to be treated during your operation, and the method
of application of ARTISS. The surgeon will determine the appropriate amount.
During your operation, the surgeon will apply ARTISS to the specific tissue using the special application device supplied. This device ensures that equal amounts of the two components of fibrin adhesive are applied simultaneously, which is important to achieve optimal results with ARTISS.
Before applying ARTISS, the wound surface must be dried using a standard technique (e.g., intermittent application of swabs or sponges, use of suction devices).
ARTISS must only be sprayed onto areas of application that are visible.
It is recommended that the initial application covers the entire surface area to be treated.

When applying ARTISS with a spray device, ensure that the pressure and distance to the tissue are within the ranges recommended by the manufacturer, as indicated below:

Pressure, distance, and equipment recommended for spray application of ARTISS

Spray

equipment to

be used

Applicator

tips to

be used

Pressure

regulator to

be used

Recommended

distance from

target tissue

Recommended

spray

pressure

Open surgery on

subcutaneous

tissue

Tisseel/Artiss

spray

applicator

n.a.

EasySpray

10–15 cm

1.5–2.0 bar

(21.5–28.5 psi)

Tisseel/Artiss

spray applicator,

10 mL container

n.a.

EasySpray

Whenever ARTISS is sprayed, and because there is a possibility of gas embolism (air or gas), changes in blood pressure, pulse, oxygen saturation, and end-tidal CO₂ levels should be monitored (see section 2).

If you use more ARTISS than you should

ARTISS will only be administered during a surgical procedure. It is applied by a surgeon, and the amount of ARTISS used will be determined by the surgeon.

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

4. Possible adverse effects

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

very common: may affect more than 1 in 10 people

common: may affect up to 1 in 10 people

uncommon: may affect up to 1 in 100 people

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

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

not known: cannot be estimated from the available data

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 previously been administered ARTISS or aprotinin during a prior surgery. Allergic reactions can be severe, so it is very important that you discuss this possibility thoroughly with your doctor.
Anaphylactic/anaphylactoid-type allergic reactions may occur; their frequency is unknown. Initial symptoms of allergic reactions may include: flushing, drop in 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 any of these symptoms are observed, administration of ARTISS must 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 damage local tissues. Frequency is unknown.
If ARTISS is injected into blood vessels (veins or arteries), blood clots (thrombosis) may occur. Frequency is unknown.
Since ARTISS is manufactured from plasma derived from blood donations, the risk of transmission of infections cannot be completely excluded, although the manufacturer takes numerous measures to reduce this risk (see section 2).
Cases of gas embolism (air or gas), which may be life-threatening or fatal (introduction of air into the bloodstream that can be serious or life-threatening), have occurred as a result of using spray devices with pressure regulators to apply fibrin tissue adhesives. These cases appear to be related to the use of spray equipment at pressures higher than recommended and/or at a very close distance to the tissue surface.

Adverse reactions reported during clinical trials of Artiss and from post-marketing experience with Baxter's fibrin tissue adhesives are described below. The known frequencies of these adverse reactions are based on a controlled clinical trial conducted in 138 patients in whom ARTISS was used to secure skin grafts to burned areas. None of the events observed in the clinical trial were classified as serious.

Table 1 Adverse reactions
Adverse reaction	Frequency
Dermal cyst	Uncommon
Pruritus	Common
Skin graft failure	Common
Air bubbles in the vascular system (gas embolism) *	Not known

*Gas or air bubbles have penetrated into the vascular system (gas embolism) in cases when fibrin sealants are applied using spray devices that use pressurized gas or air; this effect is believed to be caused by improper use of the spraying equipment (e.g., using pressures higher than recommended and spraying at 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, rapid heart rate, decrease in blood pressure, bleeding, difficulty breathing, malaise, hives, redness, impaired wound healing, inflammation, fever, accumulation of lymph and other clear 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 not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es.

By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. Storage of Artiss

Keep this medicine out of the sight and reach of children.
Do not use ARTISS after the expiry date stated on the packaging after "EXP".
Store and transport continuously frozen (at ? -20°C) until preparation for administration.
Store ARTISS in the original packaging to protect it from light.

Storage after thawing:

Unopened bags thawed at room temperature may be stored for up to 14 days at controlled room temperature (not exceeding +25°C).

Once thawed, do not refreeze or refrigerate!

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the package and other information

ARTISS contains two components:

Component 1 = Sealant Protein Solution:

The active substances contained in 1 ml of sealant protein solution are:

Human fibrinogen, 91 mg/ml produced from plasma of human donors; synthetic aprotinin, 3000 IU/ml.

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

Component 2 = Thrombin Solution:

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

Human thrombin, 4 IU/ml produced from plasma of human donors; calcium chloride dihydrate, 40 mmol/ml.

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

After mixing

1 ml

2 ml

4 ml

10 ml

Component 1: Sealing protein solution

Human fibrinogen

(as coagulable protein)

Aprotinin (synthetic)

45.5 mg

1,500 IU

91 mg

3,000 IU

182 mg

6,000 IU

455 mg

15,000 IU

Component 2: Thrombin solution

Human thrombin

Calcium chloride dihydrate

2 IU

20 mmol

4 IU

40 mmol

8 IU

80 mmol

20 IU

200 mmol

ARTISS contains human factor XIII co-purified with human fibrinogen in a range of 0.6 – 5 IU/ml.

Appearance of the product and contents of the pack

Solutions for tissue adhesive.

Frozen solutions for tissue adhesive (1 ml, 2 ml or 5 ml fibrin sealant protein solution and 1 ml, 2 ml or 5 ml thrombin solution in a single-use dual-chamber syringe contained in a bag). Unit pack.

Contents of the pack with PRIMA syringe:

1 ml, 2 ml or 5 ml of fibrin sealant protein solution and 1 ml, 2 ml or 5 ml of thrombin solution in a single-use pre-filled dual-chamber syringe (polypropylene) closed with a screw cap, packed in two bags and supplied with a device with 2 connector nozzles and 4 application cannulae.

Contents of the pack with AST syringe:

1 ml, 2 ml or 5 ml of fibrin sealant protein solution and 1 ml, 2 ml or 5 ml of thrombin solution in a single-use pre-filled dual-chamber syringe (polypropylene) closed with a screw cap, packed in two bags and supplied with a device comprising a dual syringe plunger, 2 connector nozzles, and 4 application cannulae.

The solution is colourless or pale yellow.

Only certain pack sizes may be marketed.

Marketing Authorization Holder

BAXTER, S.L.

Pouet de Camilo, 2

46394 Ribarroja del Turia (Valencia)

Spain

Tel: 962 722 800

Fax: 962 722 795

Manufacturer

Takeda Manufacturing Austria AG

Industriestraße 67

A-1221 Vienna

Austria

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

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

Artiss in DK, IS, SE.

Date of the most recent review of this summary: April 2021

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended for medical or healthcare professionals only:

Fertility, pregnancy and lactation

The safety of fibrin adhesives/hemostatics in pregnant or breastfeeding women has not been established in controlled clinical trials. Animal studies have not been conducted.

Therefore, the product should not be administered to pregnant or breastfeeding women unless strictly necessary.

The effects of ARTISS on fertility have not been established.

Dosage and method of administration

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

Dosage

The amount of ARTISS to be applied and the frequency of application should always be based on the patient's underlying clinical needs.

The dose to be administered depends on several variables, including the type of surgical procedure, the size of the area, the method of application, and the number of applications, among others.

The physician must individualize the product application. In clinical trials, individual doses have typically ranged between 0.2 and 12 ml. Larger volumes may be required in certain procedures (e.g., sealing of large burned surfaces).

An initial amount of product should be applied to the anatomical site or surface to be treated, sufficient to completely cover the desired application area. If necessary, application may be repeated on any small areas that could not be previously treated. However, reapplication of ARTISS onto an already polymerized ARTISS layer should be avoided, as ARTISS will not adhere to a polymerized layer.

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

As a guide for surface sealing, one 2 ml ARTISS pack (1 ml fibrin sealant protein solution plus 1 ml thrombin solution) will be sufficient, at minimum, for an area of 10 cm².

Skin grafts 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. After the graft or flap has been positioned, it should be held in place with gentle pressure for at least 3 minutes to ensure proper fixation of ARTISS and firm adhesion of the graft or flap 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 pack size when applied by spraying are as follows:

Approximate area requiring tissue adherence

Required Artiss container size

100 cm2

200 cm2

500 cm2

2ml

4ml

10ml

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

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

Paediatric population

Currently available data are described in section 5.1 of the Summary of Product Characteristics, but a dosing recommendation cannot be established.

Method of administration

For epidermal (topical) use only. Do not inject.

For subcutaneous use only. Use of ARTISS in laparoscopic surgery is not recommended.

To ensure safe and optimal use, ARTISS must be sprayed using a pressure-regulating device providing a maximum pressure of up to 2.0 bar (28.5 psi).

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

ARTISS should only be sprayed onto visible application sites.

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

For spray application, refer to the Administration section below.

Prior to administration of ARTISS, care must be taken to protect/cover body parts outside the application area sufficiently to prevent any tissue adhesion in unintended areas.

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

General

Before administering ARTISS, take care to cover all body parts outside the treatment area to prevent tissue adhesion in unintended areas.
To avoid adhesion of ARTISS to gloves and surgical instruments, moisten them with a sodium chloride solution prior to contact.
As a guide for surface sealing, one 2 ml ARTISS container (1 ml sealant protein solution plus 1 ml thrombin solution) will be sufficient, at minimum, for an area of 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 heat in a microwave.
DO NOT thaw the product by holding it in hands.
DO NOT use ARTISS until it has been completely thawed and warmed to 33°C – 37°C.
Remove the protective cap from the syringe only after thawing and warming are complete. To facilitate cap removal, gently rock the cap forward and backward, then remove the syringe's protective cap.
Expel all air from the syringe, then attach the connecting nozzle and application cannula.

Handling and preparation instructions

The inner pouch and its contents are sterile unless the integrity of the outer packaging is compromised. Use aseptic technique to transfer the sterile inner pouch and its contents to the sterile field.

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

Rapid thawing/warming (sterile water bath): recommended method
Thawing/warming in a non-sterile water bath
Thawing/warming in an incubator
The ready-to-use syringe may also be thawed and stored at room temperature (not exceeding 25°C) for up to 14 days. It must be warmed before use.
Rapid thawing/warming (sterile water bath), recommended method:

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

The water bath temperature must not exceed 37°C. To monitor the specified temperature range, the water temperature should be checked with a thermometer and the water changed as necessary.
If 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:

Place the inner pouch in the sterile field, 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 warming times using a sterile water bath

Container size	Minimum thawing/warming times at 33°C to 37°C, sterile water bath, product removed from the bags
2 ml	5 minutes
4 ml	5 minutes
10 ml	10 minutes

Thawing/heating in a non-sterile water bath

Instructions:

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

Table 2: Minimum thawing and warming times using a non-sterile water bath

Package size	Minimum thawing/warming times 33°C to 37°C, non-sterile water bath Product in bags
2 ml	15 minutes
4 ml	20 minutes
10 ml	35 minutes

Thawing/heating in an incubator

Instructions:

Leave the ready-to-use syringe inside both bags and place it in an incubator outside the sterile field for an appropriate period of time (see Table 3). After thawing/heating, remove the bags from the incubator, remove the outer bag, and place the inner bag containing the ready-to-use syringe into the sterile field.

Table 3: Minimum thawing and heating times in an incubator

Container size	Minimum thawing/warming times 33°C to 37°C, incubator Product in bags
2 ml	40 minutes
4 ml	50 minutes
10 ml	90 minutes

Thawing at room temperature (not exceeding +25°C) BEFORE warming:

Instructions:

Leave the ready-to-use syringe inside both bags and thaw at room temperature outside the sterile field for an appropriate period of time (see Table 4). Once thawed, to warm the product for use, heat it in the outer bag in an incubator. After thawing at room temperature, the maximum time the product may be kept (in both bags) at room temperature is 14 days.

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

Package size	Minimum thawing times at room temperature (not exceeding 25°C), followed by additional warming prior to use in an incubator at 33°C up to a maximum of 37°C Product in bags
Thawing at room temperature (not exceeding 25°C)	Warming in incubator (33°C-37°C)
2 ml	80 minutes + 11 minutes
4 ml	90 minutes + 13 minutes
10 ml	160 minutes + 25 minutes

Stability after thawing

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

For the product thawed at room temperature in the unopened bag (method 4), chemical and physical stability has been demonstrated for 14 days at temperatures not exceeding 25°C. Warm to a temperature between 33°C and 37°C immediately before use.

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

If not used immediately, the conditions and duration of storage prior to use are the responsibility of the user.

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

Handling after thawing/before application

To achieve optimal mixing of the two solutions and optimal polymerization of the fibrin tissue adhesive, keep both components at 33°C–37°C until application.

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

The thawed sealant protein solution should be a slightly viscous liquid. If the solution has a gel-like consistency, assume it has been denatured (possibly due to a break in the cold chain or excessive heat during warming). In this case, DO NOT use ARTISS under any circumstances.

Remove the syringe from the bags shortly before use.
Use ARTISS only when it has been completely thawed and warmed (liquid consistency).
Remove the syringe protective cap immediately before application.

For the PRIMA syringe: To facilitate removal of the syringe cap, gently rock the cap back and forth and then remove the syringe’s protective cap.

Non-spray administration with PRIMA syringe:

For application, the ready-to-use dual-chamber syringe containing the sealant protein solution and thrombin solution must be connected to a connecting tip and an application cannula, both included in the application device kit. The connector piece at the end of the ready-to-use dual-chamber syringe ensures that equal volumes of the two components of the tissue adhesive are expelled through the connecting tip into the application cannula, where they mix prior to application.

Instructions for use of the PRIMA syringe:

Technical diagram of a dual-chamber syringe with anchoring band, dual plunger, application cannula, and connecting nozzle

Expel all air from the syringe before connecting it to any application device.
Align the connecting tip and engage the side of the syringe into the anchoring band slot.
Connect the tips of the ready-to-use dual-chamber syringe to the connecting tip and ensure both are securely attached.
Secure the connecting tip by fastening the anchoring band to the ready-to-use dual-chamber syringe.
If the anchoring band breaks, use the spare connecting tip included in the kit.
If no spare connecting tip is available, the system may still be used provided care is taken to ensure a secure, leak-proof connection.
DO NOT expel any air remaining inside the connecting tip.
Attach an application cannula to the connecting tip.
DO NOT expel the air remaining inside the connecting tip and application cannula until the start of administration, as this could block the application cannula.

Administration

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

Apply the sealant protein-thrombin solution mixture to the surface or surfaces to be sealed by slowly pressing the common plunger’s end.
In surgical procedures requiring 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 3 minutes to allow sufficient polymerization.

Note: If the application of the fibrin tissue adhesive components is interrupted, clots may form in the cannula. In this case, replace the application cannula with a new one immediately before resuming application. If the openings of the connecting tip become blocked, use the spare connecting tip provided in the package.

BAXTER also provides other accessories suitable for application, particularly for large or hard-to-reach areas. When using these application devices, the Instructions for Use provided with the devices must be strictly followed.

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

Spray application

The pressure regulator must be used in accordance with the manufacturer's instructions.

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

Pressure, distance, and equipment recommended for spray application of ARTISS
	Spray device to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recommended spray pressure
Open-wound surgery of subcutaneous tissue	Tisseel/Artiss spray device	n.a.	EasySpray	10 – 15 cm	1.5–2.0 bar (21.5–28.5 psi)
Tisseel/Artiss spray device, 10 mL container	n.a.	EasySpray

When spraying ARTISS, changes in blood pressure, pulse, oxygen saturation, and end-tidal CO2 should be monitored to detect potential gas embolism (air or gas) (see sections 4.2 and 4.4 of the Summary of Product Characteristics).

When using accessory nozzles with this product, follow the instructions for use provided with the nozzles.

Disposal

Disposal of unused medicinal product and all materials that have come into contact with it must be carried out in accordance with local regulations.

Special precautions for disposal and other handling (final container: AST syringe)

General

Prior to administration of ARTISS, care should be taken to cover all body parts external to the treatment area to prevent unwanted tissue adhesion.
To avoid adhesion of ARTISS to gloves and surgical instruments, these should be moistened with a sodium chloride solution prior to contact.
As a guide for sealing surfaces, one 2 mL ARTISS container (1 mL fibrinogen solution plus 1 mL thrombin solution) will be sufficient, at minimum, for an area of 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 heat in a microwave.
DO NOT thaw the product by holding it in the hands.
DO NOT use ARTISS until it has completely thawed and warmed to 33°C – 37°C.
Remove the protective cap from the syringe only after thawing and warming have been completed.
Expel all air from the syringe, then attach the connecting nozzle and application cannula.

Handling and preparation instructions

The inner pouch and its contents are sterile unless the integrity of the outer packaging is compromised. Use aseptic technique when transferring the sterile inner pouch and its contents to the sterile field.

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

Rapid thawing/warming (sterile water bath), recommended method:
Thawing/warming in a non-sterile water bath
Thawing/warming in an incubator
The ready-to-use syringe may also be thawed and maintained at room temperature (not exceeding 25°C) for up to 14 days. It must be warmed prior to use.
Rapid thawing/warming (sterile water bath), recommended method:

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

The water bath temperature must not exceed 37°C. To monitor the specified temperature range, the water temperature should be checked with a thermometer and the water changed as necessary.
If a sterile water bath is used for thawing and warming, remove the pre-filled syringe from the pouches before placing it into the sterile water bath.

Instructions:

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

Package size	Minimum thawing/warming times 33°C to 37°C, sterile water bath, Product removed from bags
2 ml	5 minutes
4 ml	5 minutes
10 ml	12 minutes

Thawing/heating in a non-sterile water bath

Instructions:

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

Table 2: Minimum thawing and warming times using a non-sterile water bath

Container size	Minimum thawing/warming times at 33°C to 37°C, non-sterile water bath Product in bags
2 ml	30 minutes
4 ml	40 minutes
10 ml	80 minutes

Thawing/heating in an incubator

Instructions:

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

Table 3: Minimum thawing and heating times in an incubator

Container size	Minimum thawing/warming times 33°C to 37°C, incubator Product in bags
2 ml	40 minutes
4 ml	85 minutes
10 ml	105 minutes

Thawing at room temperature (not exceeding +25°C) BEFORE warming:

Instructions:

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

Container size	Minimum thawing times at room temperature (not exceeding 25°C), followed by additional warming prior to use in an incubator at 33°C up to a maximum of 37°C Product in bags
Thawing at room temperature (not exceeding 25°C)	Warming in incubator (33°C - 37°C)
2 ml	60 minutes + 15 minutes
4 ml	110 minutes + 25 minutes
10 ml	160 minutes + 35 minutes

Stability after thawing

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

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

If not used immediately, the conditions and duration of storage prior to use are the responsibility of the user.

Do not refreeze or refrigerate once thawing has begun.

Handling after thawing/before administration

To achieve optimal mixing of the two solutions and optimal polymerization of the fibrin tissue adhesive, maintain both components at 33°C–37°C until administration.

The sealant protein solution and thrombin solution should be clear or slightly opalescent. Do not use solutions that are cloudy or contain deposits. The thawed product should be inspected visually before use for the presence of particulate matter, discoloration, or any change in appearance. If any of these conditions are observed, discard the solutions.

The thawed sealant protein solution should be a slightly viscous liquid. If the solution has a gel-like consistency, assume it has been denatured (possibly due to a break in the cold chain or excessive heat during warming). In such cases, DO NOT use ARTISS under any circumstances.

Remove the syringe from the bags shortly before use.
Use ARTISS only when fully thawed and warmed (liquid consistency).
Remove the protective cap from the syringe immediately before administration.

Administration without spraying using the AST syringe:

For administration, the ready-to-use dual-chamber syringe containing the sealant protein solution and thrombin solution must be connected to a transfer tip and an application cannula provided in the application device kit. The common plunger of the ready-to-use dual-chamber syringe, included in the application device kit, ensures that equal volumes of the two components of the tissue adhesive are dispensed through the transfer tip into the application cannula, where they mix before administration.

Instructions for use of the AST syringe:

Diagram of a dual-chamber syringe with anchoring band, connecting nozzle, application cannula, and dual plunger

Expel all air from the syringe before connecting it to any application device.
Align the transfer tip and engage the side of the syringe into the locking band slot.
Connect the nozzles of the ready-to-use dual-chamber syringe to the transfer tip and ensure both are securely attached.
Secure the transfer tip by fastening the locking band onto the ready-to-use dual-chamber syringe.
If the locking band breaks, use the transfer tip included in the kit.
If no spare transfer tip 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 transfer tip.
Attach an application cannula to the transfer tip.
DO NOT expel the air remaining inside the transfer tip and application cannula until administration is initiated, as this may clog the cannula.

Administration

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

Apply the mixture of sealant protein solution and thrombin solution to the surface or surfaces to be sealed by slowly pressing on the back of the common plunger.
In surgical procedures requiring 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 3 minutes to achieve sufficient polymerization.

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

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

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

Spray application

The pressure regulator must be used in accordance with the manufacturer's instructions.

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

Pressure, distance, and equipment recommended for the spray application of ARTISS
	Spray applicator device to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recommended spray pressure
Open-wound surgery involving subcutaneous tissue	Tisseel/Artiss spray device	n.a.	EasySpray	10 – 15 cm	1.5–2.0 bar (21.5–28.5 psi)
Tisseel/Artiss 10 mL spray device	n.a.	EasySpray

When spraying ARTISS, monitor changes in blood pressure, pulse, oxygen saturation, and end-tidal CO2 levels to detect possible gas embolism (air or gas) (see sections 4.2 and 4.4).

When using accessory nozzles with this product, follow the instructions for use of the nozzles.

Disposal

Disposal of unused medicine and all materials that have come into contact with it should be carried out in accordance with local regulations.