Consumer medicine information

Artiss

Aprotinin; Factor XIII; Fibrinogen; Thrombin; Calcium chloride dihydrate

BRAND INFORMATION

Brand name

Artiss

Active ingredient

Aprotinin; Factor XIII; Fibrinogen; Thrombin; Calcium chloride dihydrate

Schedule

Unscheduled

What is in this leaflet?

This leaflet answers some common questions about the ARTISS Fibrin Sealant, Two-Component Fibrin Sealant, Deep-Frozen. It does not contain all of the available information. All medicines have risks and benefits. Your doctor has weighed the risks against the benefits for you having ARTISS.

It does not take the place of talking to your doctor or pharmacist. If you have any concerns about having this medicine, ask your doctor or pharmacist.

What ARTISS is used for?

ARTISS is used as a tissue glue to join skin surfaces in burns surgery. ARTISS is also used to join skin surfaces in face-lift surgery.

How does ARTISS work?

The blood coagulation factors in the composition of ARTISS are the same as those found in normal healthy individuals. They are isolated from healthy human plasma, except aprotinin, which is synthetically made. The components are packed in a double-chamber syringe. One of the chambers contains Sealer Protein solution while the other contains Thrombin solution. The double-chamber syringe is stored in a deep frozen state. It will be warmed up to between 33°C -37°C just prior to use.

Before you are given ARTISS

ARTISS should not be given to you if:

you have a tendency to allergic reactions or hypersensitivity to aprotinin or any of the ingredients in this medicine (listed under What is in ARTISS?). Some of the symptoms of an allergic reaction may include skin rash, swelling of the face, lips or tongue, which may cause difficulty swallowing or shortness of breath.
the expiry date printed on the pack has passed.

You must tell your doctor if you:

have any other illness
are taking any prescription medicine or any other medicines purchased from a pharmacy, health food store or supermarket
have previously received aprotinin or fibrin sealant, whether you are allergic or not to it

You must tell your doctor if you are pregnant, planning to become pregnant or breast-feeding.

The use of ARTISS during your surgical operation under either of these conditions is not recommended, due to insufficient information supporting such usage. If there is a need to consider the use of this product during pregnancy or breast feeding, your doctor will discuss the risks and benefits with you.

Use in Children

Safety of use in children has been established in procedures to adhere autologous skin grafts in burn patients. Safety of use in children has not been established in patients undergoing skin flaps and grafts during facial plastic and reconstructive surgeries.

How ARTISS is given

How much is given:

Your surgeon will decide how much ARTISS will be given to you, which depends on your need and condition.

How it is given:

ARTISS is for the surgeon’s use during an operation only. Your surgeon will apply it. For health professionals, details are described in the Product Information.

Case of overdose

ARTISS is used only for local application and thus the case of overdose is unlikely to occur.

While you are treated with ARTISS

Discuss with your doctor and surgeon the progress you have experienced after the treatment, especially during the first few days after surgery. As ARTISS is given in a hospital, your healthcare professional will take records of the progress and unexpected reactions.

Side effects

As with any medicine, some side effects may occur. Some patients may have sudden signs of allergy. This is more likely if the product has been used in previous surgery. Your surgeon is aware of this potential adverse effect. If any of the following happen, for example, rash, swelling of the face, lips, mouth or difficulty in breathing, tell your health professional on duty immediately. In exceptional cases symptoms of a serious allergic reaction may occur, known as “anaphylactic shock”. Then, your healthcare professional will take an appropriate action promptly to reverse the symptoms.

You must tell your doctor if you have fever, drowsiness, chills and runny nose followed by rash and joint pain that may develop about two weeks after your surgery. Similarly you must tell your doctor if you have:

dark urine
yellowed complexion, feel tired and have low grade fever followed by nausea, vomiting and abdominal pain
application site irritation
chest discomfort
chills
headache
lack of energy
restlessness
vomiting

Product description

What ARTISS looks like?

It is presented in a preloaded double-chamber syringe package under deep-frozen state.

What is in ARTISS?

The active components of ARTISS are plasma proteins isolated from pooled human blood of healthy donors according to WHO guidelines. The active components are filled in two separate chambers of a double-chamber syringe, (1) Sealer Protein solution and (2) Thrombin solution, as shown in the following Table 1.

How to store ARTISS

ARTISS is presented in a deep frozen state at –18 °C or colder in a hospital pharmacy. Under these conditions, ARTISS has a shelf life of 2 years. The cold storage chain must not be interrupted until use. Keep container in the outer carton to protect from light.

Unopened pouches, thawed at room temperature, may be stored for up to 14 days at controlled room temperature (not exceeding + 25°C). If not used within 14 days after thawing, ARTISS must be discarded. After thawing, the solution must not be refrigerated or refrozen. ARTISS solutions contain no antimicrobial agent. ARTISS Fibrin Sealant is intended for single use in one patient only and unused solution remaining in the doublechamber syringe should be discarded.

Where can you get more information?

You can get more information from your doctor or pharmacist.

Name and address of the Sponsor

ARTISS, Two component Fibrin Sealant, deep frozen, is manufactured by Baxter AG, Vienna, Austria, and supplied in Australia by:

Baxter Healthcare Pty Limited
1 Baxter Drive,
Old Toongabbie NSW 2146, Sydney

The last revision: 24 June 2013

AUST R 163515

Published by MIMS July 2017

BRAND INFORMATION

Brand name

Artiss

Active ingredient

Aprotinin; Factor XIII; Fibrinogen; Thrombin; Calcium chloride dihydrate

Schedule

Unscheduled

1 Name of Medicine

Aprotinin (synthetic), factor XIII, fibrinogen, thrombin and calcium chloride dihydrate.

2 Qualitative and Quantitative Composition

Artiss is a two-component fibrin sealant made from pooled human plasma. Each solution is presented in a separate preloaded chamber of one double-chamber syringe: chamber one [1] contains Sealer Protein Solution (with aprotinin), deep frozen (1 mL, 2 mL or 5 mL), chamber two [2] contains Thrombin Solution (with calcium chloride), deep frozen (1 mL, 2 mL or 5 mL), resulting in 2 mL, 4 mL or 10 mL total volume of product ready for use (see Tables 1 and 2).

Composition of the active ingredients of Artiss.

(1) Sealer protein solution.

1 mL of the solution contains:

Artiss contains human factor XIII co-purified with human fibrinogen in a range of 1.2-10.0 IU/mL.

(2) Thrombin solution.

1 mL of the solution contains:

List of excipients: composition of the excipients of Artiss:

Sealer protein solution.

1 mL of the solution contains human albumin (10-20 mg), histidine (10-25 mg), sodium citrate (4.8-9.7 mg), polysorbate 80 (0.6-1.9 mg), nicotinamide (3-9 mg) and water for injections q.s. to 1 mL.

Thrombin solution.

1 mL of the solution contains human albumin (45-55 mg), sodium chloride (3.5-5.5 mg) and water for injections q.s to 1 mL.

3 Pharmaceutical Form

Artiss is a two-component fibrin sealant made from pooled human plasma. The two components of Artiss are formulated as two sterile, deep-frozen solutions. The 2 components of Artiss are colourless to pale yellow, opalescent when frozen and clear to slightly turbid solutions once defrosted.

4 Clinical Particulars

4.1 Therapeutic Indications

Artiss is indicated to adhere:
autologous skin grafts in burn patients;
tissue flaps during facial rhytidectomy surgery (face lift).
Artiss is not indicated for haemostasis.

4.2 Dose and Method of Administration

Artiss should be administered topically. Do not inject.
Dry the site of application. Prior to applying Artiss, the surface area of the wound needs to be dried using standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices). Do not use pressurised air or gas for drying the site.
Artiss should be used by physicians who have been educated on or trained in the use of Artiss.
Application of the product must be individualised to the patient by the treating physician. It is recommended that the initial application cover the entire intended application area.
Repeat application may be necessary, for example, to cover a gap in an Artiss layer after initial application. In such a case, re-application of Artiss should be limited to the area of the gap itself. Application beyond the gap should be avoided as a new layer of Artiss may not adhere firmly to a layer of already polymerized Artiss from the initial application.
The skin graft should be attached to the wound bed immediately after Artiss has been applied. The surgeon has up to 60 seconds to manipulate and position the graft prior to polymerization.
After the flap or graft has been positioned, hold in the desired position by gentle compression for at least 3 minutes to ensure Artiss sets properly and the graft or flap adheres firmly to the underlying tissue.
It is strongly recommended that every time a patient receives a dose of Artiss, the name and batch number of the product are recorded in order to maintain a record of the batches used.

Cannula.

The cannulas included with the Duploject preparation and application system (Duo AST set or PRIMA set) may be used for small wounds or for edges of a skin graft that did not adhere to the wound bed.
Immediately before application, expel and discard the first several drops from the application cannula to ensure adequate mixing of the sealer protein and thrombin solutions.
The wound surface should be as dry as possible before application of Artiss. Apply Artiss thinly (2 mL/100 cm²) to avoid formation of excessive granulation tissue and interference with wound healing.
If application is interrupted, clogging will occur quickly in the cannula. Replace the application cannula with a new one only immediately before application is resumed. If the aperture of the joining piece (Y connector) facing the cannula is clogged, use the spare joining piece provided in the package.

Spray set.

For large surface areas, spray application is recommended. The required dose of Artiss depends on the size of the surface to be covered. The approximate surface areas covered by each package size of Artiss by spray application (see Table 3).

This recommended dose applies to all age groups.

Method of preparation of Artiss preloaded syringe (frozen).

Unopened pouches, thawed at room temperature, may be stored for up to 14 days at controlled room temperature (not exceeding + 25°C). If not used within 14 days after thawing, Artiss must be discarded.
To facilitate optimal blending of the two solutions, the two sealant components must be warmed to 33-37°C immediately before use.
Artiss must not be exposed to temperatures above 37°C and must not be microwaved.
After quick thawing (i.e. thawing at a temperature of 33-37°C), Artiss may be stored at 33-37°C for a maximum of 4 hours.
To prevent Artiss from adhering, wet gloves and instruments with sodium chloride solution before contact.
Do not use Artiss unless it is completely thawed and warmed (liquid consistency). The protective syringe cap should not be removed until storage, thawing and warming is complete and application tip is ready to be attached.
For quick thawing of the preloaded syringe use one of the three following options.

Option 1. Thawing on the sterile field.

33°C to 37°C sterile water bath: transfer devices set and the inner pouch to the sterile field, remove devices set with preloaded syringes from inner pouch and place directly into sterile water bath. Ensure the contents of the syringe are completely immersed under the water. Approximate thawing and warming times when using this method (see Table 4).

Option 2. Thawing off the sterile field using water bath.

33°C to 37°C nonsterile water bath in two pouches: maintain the devices set in both pouches and place into a water bath off the sterile field for appropriate time. Ensure the pouches remain submerged throughout thawing. Remove from the water bath after thawing, dry external pouch and transfer inner pouch and preloaded syringe onto the sterile field. Approximate thawing and warming times when using this method (see Table 5).

Option 3. Thawing off the sterile field using incubator.

Incubator (33°C to 37°C) in pouches: maintain the devices set in both pouches and place into an incubator for appropriate time. Remove from incubator after thawing and transfer inner pouch and preloaded syringe onto the sterile field. Approximate thawing and warming times when using this method (see Table 6).

Operating instructions.

Cannula.

For application, the double chamber syringe with the sealer protein solution and the thrombin solution has to be connected to a joining piece and an application cannula as provided in the accompanying set of devices. The common plunger of the double chamber syringe ensures that equal volumes are fed through the joining piece before being mixed in the application cannula and ejected.
Device set instructions: firmly connect the double chamber syringe nozzles to the Y-piece and secure it by fastening the tether strap to the syringe. Fit an application cannula onto the Y-piece. To avoid clogging, do not expel the air remaining inside the Y-piece or application cannula until application.

Spray set.

See package insert of the spray set for instructions on administration of Artiss using the spray set.
Air embolism has occurred with the use of a spray device to administer fibrin sealant (see Section 4.8 Adverse Effects (Undesirable Effects)). This appears to be related to the use of the spray device at higher than recommended pressures and in close proximity to the tissue surface.
Caution must be used when applying fibrin sealant using pressurized air or gas.
Any application of pressurized air or gas is associated with a potential risk of air or gas embolism, tissue rupture, or gas entrapment with compression, which may be life threatening or fatal.
Life threatening/ fatal air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressure and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO₂ and therefore cannot be excluded with Artiss when sprayed in open wound surgery.
Artiss with the spray set must not be used in enclosed body areas.
Artiss must be sprayed only onto application sites that are visible.
Artiss must not be applied intravascularly.
The user must follow the instructions and precautions in the easy spray device user manual, for example regarding the need to limit the gas pressure to a maximum of 2 bars and not be sprayed if the distance is closer than 10 cm from the tissue surface.
To reduce the risk of a potentially life threatening gas embolism when applying Artiss using a spray device, be sure to use a pressure within the pressure range recommended by the spray device manufacturer. Artiss spray application should only be used if it is possible to accurately judge the spray distance and do not spray if the distance is closer than recommended by the manufacturer.
Only use application devices licensed/ CE Marked for the administration of Artiss.
When spraying Artiss, changes in blood pressure, pulse, oxygen saturation and end tidal CO₂ should be monitored because of the possibility of air or gas embolism (see Section 6.2 Incompatibilities).

4.3 Contraindications

Known hypersensitivity to aprotinin or known hypersensitivity to any other component of Artiss.
Injection of Artiss into tissues is contraindicated. Such use has been associated with inadvertent intravascular injection, with thromboembolic complications. Artiss should be applied with caution to minimise any risk of intravascular application. Artiss should only be applied topically.
Additionally, soft tissue injection of Artiss carries the risk of an anaphylactic reaction and/or local tissue damage.

4.4 Special Warnings and Precautions for Use

Viral and prion risk.

Sealer protein solution and thrombin solution are made from human plasma. Products made from human plasma may contain infectious agents which can cause disease, such as viruses and theoretically, the agent that causes Creutzfeldt-Jakob disease (CJD) in humans. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/ removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses or other pathogens.
The measures taken are considered effective for inactivation/ removal of enveloped viruses such as HIV, HBV, and HCV, and for the non-enveloped virus HAV. The measures taken may be of limited value against small non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased red blood cell turnover (e.g. haemolytic anaemia).
All infections thought by a clinician possibly to have been transmitted by Artiss should be reported by the clinician or other healthcare provider to Baxter.
Patients should be instructed to consult their clinician if symptoms of B19 virus infection appear (fever, drowsiness, chills and runny nose, followed about two weeks later by a rash and joint pain).

General.

Administration of Artiss may result in allergic reactions in some patients. For patients with a known allergic diathesis, a history of hypersensitivity to medical products or a history of having previously received aprotinin containing products (including previous use of Artiss) a careful risk/ benefit assessment should be carried out prior to administration. The risk of immunisation against proteins such as aprotinin is increased if repeated exposure occurs within six months. If it is decided to proceed with treatment in such patients, prior administration of antihistamines should be considered.
Manifestations of hypersensitivity reactions to Artiss observed include: bradycardia, tachycardia, hypotension, flushing, bronchospasm, wheezing, dyspnoea, nausea, urticaria, angioedema, pruritus, erythema, paraesthesia. Fatal anaphylactic reactions, including anaphylactic shock, have also been reported with Artiss (see Section 4.8 Adverse Effects (Undesirable Effects)). Intravascular application might increase the likelihood and severity of acute hypersensitivity reactions in susceptible patients. Because of the risk of intravascular injection, the product must not be injected into highly vascularised tissue, such as nasal mucosa.
Artiss contains synthetic aprotinin. As synthetic aprotinin is structurally identical to bovine aprotinin, the use of Artiss in patients with allergies to bovine proteins should be carefully evaluated.
Air or gas embolism, tissue rupture, or gas entrapment with compression, which may be life threatening, have occurred with the use of spray devices employing a pressure regulator to administer Artiss. These events appear to be related to the use of the spray device at higher than recommended pressures and in close proximity to the tissue surface.
To reduce the risk of a potentially life threatening gas embolism, when applying Artiss using a spray device, be sure to use the pressure within the pressure range recommend by the spray device manufacturer. In the absence of a specific recommendation avoid using pressure above 1.4-1.7 bars (20-25 psi). Do not spray if the distance is closer than the distance recommended by the spray device manufacturer. In the absence of a specific recommendation avoid spraying closer than 10-15 cm from the surface of the tissue. When spraying Artiss, changes in blood pressure, pulse, oxygen saturation and end tidal CO₂ should be monitored because of the possibility of occurrence of air or gas embolism.
As the sealer protein and thrombin solutions can be denatured following contact with solutions containing alcohol, iodine or heavy metals (e.g. in disinfectants), any such substances should be removed before application (see Section 6.2 Incompatibilities).
If possible, cover all tissue adjacent to the site of sealing before applying Artiss.
Apply Artiss in a thin layer. Excessive clot thickness may interfere with the product's efficacy and the wound healing process.

Use in the elderly.

Thirteen subjects aged 65 and older (40-71 years of age) have been treated with Artiss in facial rhytidectomy clinical studies. Separate evaluations of these subjects were not performed.

Paediatric use.

In the burns setting, efficacy and safety in the paediatric population was not different from the adult population.

Effects on laboratory tests.

The effect of this medicine on laboratory tests has not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Artiss. No known interactions based upon the absence of data from clinical trials, current medical/ scientific literature, and postmarketing safety reports. See Section 6.2 Incompatibilities for more detailed information on interactions with substances other than drugs.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies of the effect of Artiss on fertility have not been performed.
(Category B2)
The safety of Artiss for use in human pregnancy has not been established in controlled clinical studies. Animal studies have also not been performed. Physicians should carefully consider the potential risks and benefits for each patient before prescribing Artiss.
Therefore, the product should be administered to pregnant women only if clearly needed. See Section 4.4 Special Warnings and Precautions for Use, Viral and prion risk for information on parvovirus B19 infection.
The safety of Artiss for use in breastfeeding has not been established in controlled clinical studies. Animal studies have also not been performed. Physicians should carefully consider the potential risks and benefits for each patient before prescribing Artiss. Therefore, the product should be administered to lactating women only if clearly needed.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions from clinical trials.

In a phase 3, multicentered, prospective, evaluator blinded, randomised study, where Artiss was used to affix split thickness sheet skin grafts to excised burn wounds, a total of 8 nonserious adverse reactions were reported. There were no serious reactions.
The eight nonserious adverse reactions occurred in six patients. Five of these reactions were skin graft failures, 4 were graft detachment/ nonadherence, and 1 was graft necrosis. The remaining nonserious adverse reactions were pruritus (2) and dermal cyst (1) (see Table 7).

There were no reports of serious, associated adverse reactions reported above 1% in the facial rhytidectomy clinical studies.

Postmarketing adverse reactions.

There are limited postmarketing data available for Artiss. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
Adverse reactions reported from clinical studies as well as from postmarketing surveillance of Baxter's other fibrin sealants are summarised in the following. Unknown frequencies are based on spontaneous reports from postmarketing surveillance of Baxter's fibrin sealants.

Immune system disorders.

Frequency unknown: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock, and the following manifestations: angioedema, paraesthesia, bradycardia, tachycardia, flushing, bronchospasm, dyspnoea, wheezing, urticaria, pruritus, and erythema). Anaphylactic reactions and anaphylactic shock have included fatal outcomes.

Cardiac disorders.

Frequency unknown: bradycardia, tachycardia.

Vascular disorders.

Frequency unknown: hypotension, haematoma and air embolism^*.
^*Air embolism associated with misapplication of fibrin sealant using a spray device. There are reports of life threatening/ fatal air or gas embolism associated with the use of fibrin sealants when applied using a spray device at higher than the recommended pressure and closer than the recommended distance in an attempt to stop active bleeding.

Respiratory, thoracic and mediastinal disorders.

Frequency unknown: dyspnoea.

Gastrointestinal disorders.

Frequency unknown: nausea.

Skin and subcutaneous tissue disorders.

Common: pruritus. Uncommon: dermal cyst. Frequency unknown: urticaria.

General disorders and administration site conditions.

Frequency unknown: flushing, impaired healing, oedema, pyrexia.

Injury, poisoning and procedural complication.

Common: skin graft failure. Frequency unknown: seroma.

Class reactions.

Manifestations of hypersensitivity or allergic reactions associated with the class of fibrin sealant/haemostatic products include: application site irritation, chest discomfort, chills, headache, lethargy, restlessness and vomiting. There have been no reports of these reactions related to the specific use of Artiss.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

To avoid the formation of excess granulation tissue and to ensure gradual absorption of the solidified fibrin sealant, only a thin layer of the mixed Sealer Protein Thrombin Solution or the individual components should be applied.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: local haemostatics, ATC code: B02BC; Pharmacotherapeutic group: tissue adhesives, ATC code: V03AK.
Artiss contains two components, sealer protein solution and thrombin solution. The sealer protein solution contains fibrinogen as the main active ingredient, and the active ingredient of the thrombin solution is human thrombin. These mimic the final step of the coagulation cascade.
The thrombin converts fibrinogen to fibrin which then polymerises and is crosslinked by factor XIIIa to form a clot. Due to the low concentration of thrombin in Artiss, clotting takes about a minute. Clotting causes tissues to adhere and provides a matrix for the in growth of fibroblasts and capillaries which helps vascularisation and wound healing. The matrix is eventually broken down and absorbed in a process called fibrinolysis. Aprotinin in Artiss delays fibrinolysis.
Figure 1 illustrates the conversion of fibrinogen to fibrin, and polymerization.

Artiss containing 4 IU thrombin has demonstrated adhesion of autologous split skin grafts to surgically prepared wound beds in a pig model.

Clinical trials.

Burns (grafts).

Artiss (frozen) was investigated for fixation of split thickness sheet skin grafts in burn patients in a prospective, randomised, controlled, multicentre clinical study, conducted in 138 burn subjects. In each subject, two comparable test sites were identified. In one test site the skin graft was fixed with Artiss; in the other test site the graft was fixed with staples (control).
The intent to treat (ITT) population reported in the study report included 127 of the treated subjects. The 11 treated subjects not included in the study ITT population were excluded for one of the following reasons: no primary endpoint assessment at both test sites (one subject); lost to follow-up prior to day 28; or photographs not taken at both test sites on day 28. The median age of subjects was 31 years, range 1-62 years, 14% were ≤ 6 years of age and 15% 7-18 years of age, 66% of the subjects were male. Similar areas were treated at the two sites: 1.7 ± 0.8% body surface area at Artiss sites and 1.7 ± 0.7% body surface area at stapled sites. Burn thickness was full in 77% of subjects and partial in 23%. The most commonly grafted sites were the lower arms and lower legs.
Artiss proved to be noninferior to staples with respect to the primary efficacy endpoint, complete wound closure at day 28 using a one sided 97.5% confidence interval on the difference in the proportion of test sites successfully treated. Wound closure was evaluated by a blinded evaluator panel from day 28 photographs. Results for wound closure on day 28 are given in Table 8.

There was support from the secondary endpoints which were evaluated by the investigator (see Table 9).

Facial rhytidectomy (flaps).

Artiss was investigated for adherence of skin flaps in facial rhytidectomy surgeries during two prospective, randomised, controlled, multicenter clinical studies. Both studies had a split face design in which one side of the face was treated with Artiss and the other side received standard of care (SoC); therefore each subject participated in both arms (Artiss and SoC). In the phase 2 study, ecchymosis evaluation was performed by an independent panel of 5 blinded reviewers. In both the phase 2 and phase 3 studies, a standardised drain was placed in each side of the face prior to the flap closure and drainage volume from both sides of the face from all subjects was used to compare adherence. Pressure dressings were not permitted.
The combined study population consisted of 120 subjects of which 113 (94.2%) were female and 7 (5.8%) were male. The mean ± SD age was 54.7 ± 7.2 years (range: 40-71 years). The mean ± SD weight was 66.5 ± 11.9 kg. By race, 116 (96.7%) were white, 2 (1.7%) were black, 1 (0.8%) was Asian, and 1 (0.8%) was of multirace. Ethnicity was Hispanic or Latino in 5 (4.2%) subjects. Overall, the demographic and baseline characteristics were similar for both studies, allowing comparison of appropriate efficacy outcomes.
The endpoints analysed for the two studies are: drainage volumes at 24 h postoperatively, for each side of the face (see Table 10) and occurrence of haematoma and seroma (see Table 11).

An integrated analysis of the occurrence of haematoma/seroma in all 120 subjects across two studies was performed. A comparison was made of the proportion of subjects experiencing a haematoma/seroma exclusively on the Artiss treated side or on the SoC side of the face. The difference was statistically significant with 95% CI=0.035-0.172, p < 0.05.

5.2 Pharmacokinetic Properties

Artiss is intended for topical use only. Intravascular administration is contraindicated. As a consequence, intravascular pharmacokinetic studies were not performed in man.
Fibrin sealants/haemostatics are metabolised in the same way as endogenous fibrin by fibrinolysis and phagocytosis.

5.3 Preclinical Safety Data

Genotoxicity.

Studies of genotoxic potential of Artiss have not been performed.

Carcinogenicity.

Animal studies to evaluate the carcinogenic potential of Artiss have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Solutions containing alcohol, iodine or heavy metals will interfere with the product's performance due to denaturation of proteins or other mechanisms. If any of these substances have been used to clean the wound area; the area must be thoroughly rinsed and dried before application of Artiss.
Oxidised cellulose-containing preparations may reduce the efficacy of Artiss and should not be used as carrier materials.
Artiss must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Deep frozen Artiss has a shelf life of two years when stored at -18°C or colder. The expiry date is stated on the final container and the package.

6.4 Special Precautions for Storage

Store in a freezer at -18°C or colder. The cold storage chain must not be interrupted until use. Keep container in the outer carton to protect from light.
Unopened pouches, thawed at room temperature, may be stored for up to 14 days at controlled room temperature (not exceeding +25°C). If not used within 14 days after thawing, Artiss must be discarded. After thawing, the solutions must not be refrigerated or refrozen.
After quick thawing (i.e. thawing at a temperature of 33-37°C), Artiss may be stored at 33-37°C for a maximum of 4 hours.
Once thawed, do not refreeze or refrigerate. Keep out of reach and sight of children. For single use only. Do not re-sterilise.

6.5 Nature and Contents of Container

Nature of containers.

Both Sealer Protein Solution and Thrombin Solution are contained in two separate chambers of a single use double chamber syringe made of polypropylene.

Contents.

Each pack Artiss contains:
one single use double chamber syringe, each chamber containing: Chamber number [1] Sealer Protein Solution (with aprotinin) deep frozen; Chamber number [2] Thrombin Solution (with calcium chloride) deep frozen.
one set of devices (see below).

Set of devices.

Each pack of Artiss contains a double-sterile set of devices (AST or PRIMA) consisting of one syringe double-plunger, two Y-pieces and four application cannulas. These devices are used for the simultaneous application of the fibrin sealant components. For details on application and complications associated therewith see Section 4.2 Dose and Method of Administration, Operating instructions.
The set of devices is sterile and non-pyrogenic in unopened and undamaged package. Sterilised by exposure to ethylene oxide.
Artiss is available in the following pack sizes: Artiss, 2.0 mL (containing 1.0 mL of Sealer Protein Solution and 1.0 mL of Thrombin Solution); Artiss, 4.0 mL (containing 2.0 mL of Sealer Protein Solution and 2.0 mL of Thrombin Solution) and Artiss, 10.0 mL (containing 5.0 mL of Sealer Protein Solution and 5.0 mL of Thrombin Solution).

Package size.

2 mL, 4 mL, 10 mL.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.
The Artiss solutions contain no antimicrobial agent. Artiss is intended for single use in one patient only and unused solution in the syringe should be discarded.

6.7 Physicochemical Properties

Fibrinogen.

Chemical structure.

The major component of the clottable protein (human origin) is fibrinogen. The fibrinogen molecule is a dimer composed of two symmetrical subunits linked by -S-S-bonds. It could be written in a simple formula as (Aα, Bβ, γ)₂. Molecular weight (MW): 340,000. The Aα-chain contains 610 amino acids (MW about 68,000), the Bβ-chain 461 amino acids (MW about 57,000), and the γ-chain 411 amino acids (MW about 47,000). Thus, the entire human fibrinogen contains 2964 amino acids.

CAS number.

9001-32-5.

Thrombin.

Chemical structure.

Thrombin (human origin) is a glycosylated protein, consisting of two polypeptide subunits A and B, covalently linked by one -S-S-bond.
Molecular weight (MW): 33,800. The human thrombin subunit A chain is made of 36 amino acids, whilst the B chain contains 259 amino acids.

CAS number.

9002-04-4.

Factor XIII.

Chemical structure.

Factor XIII (human origin), also called blood-coagulation factor XIII, is a tetramer composed of two a-chains and two b-chains, which are non-covalently associated.
Molecular weight (MW): about 190,000 (each of a molecular weight of about 80,000).

CAS number.

9013-56-3.

Aprotinin.

Chemical structure.

Aprotinin (synthetic origin) is a protease inhibitor, a polypeptide consisting of one chain of 58 amino acids stabilised by -S-S-bonds.
Molecular weight (MW): 6511.5.

CAS number.

9087-70-1.

Calcium chloride dihydrate.

Molecular formula: CaCl₂.2H₂O.
Molecular weight: 147.01.

CAS number.

10035-04-8.
Appearance: a white crystalline powder.
Solubility: hygroscopic, freely soluble in water.

7 Medicine Schedule (Poisons Standard)

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Aprotinin; Factor XIII; Fibrinogen; Thrombin; Calcium chloride dihydrate

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