Baxter

PATIENT INFORMATION LEAFLET

Tisseel Lyo

Two-Component Fibrin Sealant

What is TISSEEL Lyo, and what is it used for?

The name of your medicine is Tisseel Lyo.

Tisseel Lyo is a two-component fibrin sealant, and it contains two of the proteins that make blood clot. These proteins are called fibrinogen and thrombin. When these proteins mix during application, they form a clot where the surgeon applies them.

Tisseel Lyo is prepared as two solutions, which mix when applied. When prepared, 1 ml of each solution contains the following:

-    Human fibrinogen (as clottable protein), 72 - 110 mg in 96 - 125 mg protein; aprotinin (synthetic), 3000 KIU per ml. Inactive ingredients include human albumin, L-Histidine, niacinamide, polysorbate 80, sodium citrate dihydrate and water for injections

-    Human thrombin, 500 IU, in 45 - 55 mg protein; calcium chloride, 40 micromol/litre. Inactive ingredients include human albumin and sodium chloride (salt).

Tisseel Lyo is applied during surgery, to the surface of tissues.

Tisseel Lyo is available in presentations of 2 ml, 4 ml and 10 ml.

The Company responsible for the product (Marketing Authorisation Holder) is Baxter Healthcare Ltd, Caxton Way, Thetford IP24 3SE.

The Manufacturer is Baxter AG, Industriestrasse 67, A-1221 Vienna

1. WHAT IS TISSEEL Lyo USED FOR?

Tisseel Lyo is a fibrin sealant. During surgery, tissues may bleed or ooze, and it may not be possible for the surgeon to control this bleeding using stitches, or by applying pressure. Tisseel Lyo is applied to tissues either to control bleeding, or to stop (or prevent) leaks of other types of fluid by creating a watertight seal.

Tisseel Lyo can be used even if your blood does not clot properly, such as occurs when you are treated with heparin. It is also used as a tissue glue to achieve adhesion/sealing or as suture support in surgery.

In addition, Tisseel Lyo is used to fix mesh during hernia repair surgery.

The clot produced by Tisseel Lyo is very similar to a natural blood clot and this means that it will dissolve naturally and leave no residue. However, synthetic aprotinin is added to increase the longevity of the clot and to prevent its premature dissolution.

2. BEFORE RECEIVING TISSEEL Lyo

What should I check before receiving TISSEEL Lyo?

Certain people should avoid receiving Tisseel Lyo. If any of the following apply to you, you should tell your doctor.

•    Have you reacted to drugs or other products produced from cattle?

•    Have you ever suffered from a reaction to any of the products listed in the ingredients of Tisseel Lyo?

Tisseel Lyo is not suitable on its own for treating active or spurting bleeding from arteries or veins. It is not to be applied inside blood vessels.

When should I/my surgeon be careful about using TISSEEL Lyo?

•    Life-threatening/fatal air or gas embolism (air getting into the blood circulation which can be serious or life-threatening) has occurred very rarely with the use of spray devices employing pressure regulators to administer fibrin sealants. This appears to be related to the use of the spray device at higher than recommended pressures 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 TISSEEL Lyo when sprayed in open wound surgery.

•    Spray devices and the accessory tip provide instructions for use with recommendations for pressure ranges and to the spraying distance from the tissue surface.

•    TISSEEL Lyo should be administered strictly according to the instructions and only with devices recommended for this product.

•    When spraying TISSEEL Lyo, changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored for possible occurrence of gas embolism.

Certain people are very sensitive to medicines in general, and may react to Tisseel Lyo being applied. If you think this applies to you, please discuss this with your doctor.

Tisseel Lyo MUST NOT be injected into blood vessels (veins or arteries), or into tissues. As Tisseel Lyo forms a clot where it is applied, injecting Tisseel Lyo may cause serious reactions. Tisseel Lyo should only be applied to the surface of tissues as thin layer where it is needed.

-    Tisseel Lyo contains a synthetic protein, called aprotinin. Even when this protein is applied in small areas, there is a risk of a reaction known as anaphylaxis, or a severe allergic reaction. This risk is increased in patients who have received aprotinin before, even if there was no reaction to the first application. It is very important that the hospital staff who treat you record in your notes when you have received aprotinin, or Tisseel Lyo.

-    If you have ever received Tisseel Lyo or aprotinin before, your body may have become sensitive to it, and it is possible you have an allergy. If you think you have received either product in a previous operation, please talk to your doctor about this.

-    If the surgeon or operating team sees any sign of an allergic reaction when they apply Tisseel, the use of Tisseel Lyo should be stopped immediately. Early symptoms of allergic reactions can be: flushing, a fall in blood pressure, increased or decreased pulse rate, nausea (feeling sick), hives, itching, difficulty breathing.

-    Tisseel Lyo must NOT be injected into blood vessels (veins or arteries), or into tissues. As Tisseel Lyo forms a clot where it is applied, injecting Tisseel Lyo may cause serious complications. Tisseel Lyo should only be applied to the surface where it is needed. In particular your surgeon should apply Tisseel Lyo with special care if you are having coronary bypass surgery (surgery to replace diseased arteries) to minimize the risk of the product going into your blood vessels.

-    Some solutions that contain alcohol, iodine or certain types of metals (these are normally found in disinfectants or antiseptics) may reduce the ability of Tisseel Lyo to work normally. These substances should be removed, as far as possible, before Tisseel Lyo is applied.

Tisseel Lyo is made from the plasma taken from blood donations. When medicinal products prepared from human blood or plasma are administered, the transmission of infections (or diseases) cannot be totally ruled out. This applies to diseases we already know about, and also those that have not yet been discovered.

To reduce the risk of infections being transmitted, donors are selected very carefully, and all donations are tested. Each donation is tested to ensure that the donor is not infected with HIV (the virus that causes AIDS), or the viruses Hepatitis A, B or C (that cause liver disease).

As a further safety measure, there are processes during manufacturing that are designed to remove or kill viruses in the raw materials. However, these methods are not completely effective against Parvovirus B19 - it is still possible that these diseases could be transmitted if they were present in the original plasma donation.

In healthy people, Parvovirus B19 infection can cause a mild illness which may result in a facial rash which lasts for about a week. It may also cause joint pain which can last for a few weeks, but it is not harmful to the joints themselves. In people with immune deficiencies (when the immune system does not make antibodies properly), the virus can cause chronic anaemia - this can be controlled or cured by treatment with other medicines. If a pregnant woman is infected with Parvovirus B19, there is a small risk (less than one in ten) of it causing a miscarriage. Most adults carry antibodies to Parvovirus B19.

It is strongly recommended that the hospital staff who treat you record the name and batch number of the product in your notes.

Pregnancy and Breast-feeding:

If you are pregnant, or think you may be pregnant, or if you are breast-feeding you should tell your doctor. Please see Section 2 regarding the risks of Parvovirus B19 during pregnancy.

As Tisseel Lyo is only used during surgical operations, if you are pregnant you should discuss the overall risks of the operation with your doctor.

Driving and using machines:

As you will be in hospital when Tisseel Lyo is applied, it is not possible for Tisseel Lyo to affect your ability to drive or operate other types of machine.

Taking or Using other Medicines:

It is not thought that Tisseel Lyo affects the action of other drugs, however you should always tell your doctor about any medicines or dietary supplements you are taking (for example, vitamins, St John’s Wort), even those you have bought yourself from a chemist or supermarket.

3. HOW SHOULD TISSEEL Lyo BE USED?

•    Tisseel Lyo is only applied during a surgical operation. The use of TISSEEL Lyo is restricted to experienced surgeons who have been trained in the use of TISSEEL Lyo.

•    The amount of Tisseel Lyo that will be used depends on a number of factors, including the type of surgery, the surface area of tissue to be treated during your operation and the way Tisseel Lyo is applied. The surgeon will decide how much is appropriate, and will apply just enough to form a thin, even layer over the tissue. If this does not seem to be enough, a second layer can be applied.

•    During your operation the surgeon will apply Tisseel Lyo onto the relevant tissue surface, using the special application device provided. This device ensures that equal amounts of both components are applied at the same time - this is important for Tisseel Lyo to have its optimal effect.

•    For hernia mesh repair the surgeon will apply Tisseel using spray or drops to fix the mesh in place.

•    Specially trained staff from Baxter Healthcare will have trained the theatre nurses and the surgeon in how to prepare and use Tisseel Lyo properly, before your operation takes place.

•    Prior to applying TISSEEL Lyo the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

When applying TISSEEL Lyo using a spray device be sure to use a pressure and a distance

from the tissue within the range recommended by the manufacturer as follows:

Recommended pressure, distance and devices for spray application of TISSEEL Lyo
Surgery	Spray set to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recom mended spray pressure
Open wound	Tisseel / Artiss Spray Set	n.a.	EasySpray	10 - 15 cm	1.5 - 2.0 bar (21.5 -28.5 psi)
	Tisseel / Artiss Spray Set 10 pack	n.a.	EasySpray

		Duplospray MIS Applicator 20 cm	Duplospray MIS Regulator
			Duplospray MIS Regulator NIST B11
		Duplospray MIS Applicator 30 cm	Duplospray MIS Regulator
Laparo- scopic/ minimally invasive procedures	n.a.		Duplospray MIS Regulator NIST B11	2 - 5 cm	1.2 - 1.5 bar
		Duplospray MIS Applicator 40 cm	Duplospray MIS Regulator		(18 - 22 psi)
			Duplospray MIS Regulator NIST B11
		Replaceable tip	Duplospray MIS Regulator
			Duplospray MIS Regulator NIST B11

When spraying the TISSEEL Lyo, 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 (see section 2).

Overdose

As Tisseel Lyo is only ever applied by a surgeon, we do not think it is possible to use too much.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Tisseel Lyo can have side effects.

•    There is a slight possibility of you having an allergic reaction to one of the components of Tisseel Lyo. This is more likely if you have been treated with Tisseel Lyo or aprotinin during a previous operation. Allergic reactions can be serious, and it is very important that you discuss this possibility in detail with your doctor.

•    In very rare cases anaphylactic/anaphylactoid reactions, such as difficulty in breathing, a tight chest, flushing of the face and skin, a sensation of heat or rash may occur.

•    Early symptoms of allergic reactions can be: flushing, a fall in blood pressure, increased or decreased pulse rate, nausea (feeling sick), hives, itching, difficulty breathing.

•    The surgical team treating you will be aware of the risk of this type of reaction - if they see any of the symptoms mentioned above, they will stop applying Tisseel Lyo immediately. Severe symptoms may require an immediate emergency treatment.

•    If Tisseel Lyo is injected into soft tissues, it can cause anaphylactoid reactions (similar to anaphylaxis) and / or local tissue damage.

•    If Tisseel Lyo is injected into blood vessels (veins or arteries), it can cause clots to form (thrombosis) and / or anaphylactic reactions.

•    As Tisseel Lyo is made from the plasma taken from blood donations, there is a risk of infection (see section 2).

If you feel unwell after your operation, and the symptoms do not match those that your doctor

has already told you about, then you should speak to your doctor immediately.

5.    STORING TISSEEL Lyo

•    Keep out of the reach and sight of children.

•    Store at +2°C - +25°C. Do not freeze.

•    Store in the original package in order to protect from light.

•    Do not use after the expiry date stated on the label.

6.    FURTHER INFORMATION Date of Revision: 03/2013

Remember: This medicine is only for you, only a doctor can prescribe Tisseel Lyo for you. Never give medicines prescribed for you to anyone else.

INSTRUCTIONS FOR MEDICAL OR HEALTHCARE PROFESSIONALS ONLY

When applying TISSEEL Lyo using a spray device be sure to use a pressure and a distance from the tissue within the range recommended by the manufacturer as follows:

Recommended pressure, distance and devices for spray application of TISSEEL Lyo
Surgery	Spray set to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recom mended spray pressure
Open wound	Tisseel / Artiss Spray Set	n.a.	EasySpray	10 - 15 cm	1.5 - 2.0 bar (21.5 -28.5 psi)
	Tisseel / Artiss Spray Set 10 pack	n.a.	EasySpray

		Duplospray MIS Applicator 20 cm	Duplospray MIS Regulator
			Duplospray MIS Regulator NIST B11
		Duplospray MIS Applicator 30 cm	Duplospray MIS Regulator
Laparo scopic/ minimally invasive procedures	n.a.		Duplospray MIS Regulator NIST B11	2 - 5 cm	1.2 - 1.5 bar
		Duplospray MIS Applicator 40 cm	Duplospray MIS Regulator		(18 - 22 psi)
			Duplospray MIS Regulator NIST B11
		Replaceable tip	Duplospray MIS Regulator
			Duplospray MIS Regulator NIST B11

When spraying the TISSEEL Lyo, 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 (see section 2).

B&xter

SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

TISSEEL Lyo

Two-Component Fibrin Sealant

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each TISSEEL Lyo contains 4 vials. The active ingredients are:

•    Sealer Protein Concentrate Lyophilized for Sealer Protein Solution, Human, Vapour Heated, S/D treated

After reconstitution of the powder, 1 ml of Sealer Protein Solution contains:

Total protein 96 - 125 mg of which 72 - 110 mg is Fibrinogen (as clottable protein).

•    Aprotinin Solution, Solvent for Sealer Protein Concentrate Lyophilized, Aprotinin, synthetic 3000 KlU’/ml

•    Human Thrombin Lyophilized for Thrombin Solution, Human, Vapour Heated, S/D treated After reconstitution of the powder, 1 ml of Thrombin Solution contains:

500 IU² of Thrombin in 45 - 55 mg of Total protein.

•    Calcium Chloride Solution, Solvent for Thrombin Powder Ca²+ 40 pmol/ml

3.    PHARMACEUTICAL FORM

Powders and solvents for fibrin sealant.

One TISSEEL Lyo contains all the substances required for the preparation of the two fibrin sealant components and the kit for reconstitution and application (for details see Section 6.5. Nature and Contents of Containers).

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Supportive treatment where standard surgical techniques are insufficient

-    for improvement of haemostasis (see section 5.1)

-    as a tissue glue to promote adhesion/sealing or as suture support:

-    in gastrointestinal anastomoses

-    in neurosurgery where contact with cerebro-spinal fluid or dura mater can occur

-    For mesh fixation in hernia repair, as an alternative or adjunct to sutures or staples.

4.2.    Posology and method of administration

The use of TISSEEL Lyo is restricted to experienced surgeons who have been trained in the use of TISSEEL Lyo.

Posology

The amount of TISSEEL Lyo to be applied and the frequency of application should always be oriented towards the underlying clinical needs for the patient.

The dose to be applied is governed by variables including, but not limited to, the type of surgical intervention, the size of the area and the mode of intended application, and the number of applications.

To avoid the formation of excess granulation tissue and to ensure gradual absorption of the solidified fibrin sealant, only a thin layer of TISSEEL Lyo should be applied.

Application of the product must be individualized by the treating physician. In clinical trials, the individual dosages have typically ranged from 4 to 20 ml. For some procedures, larger volumes may be required.

The initial amount of the product to be applied at a chosen anatomic site or target surface area should be sufficient to entirely cover the intended application area. The application can be repeated, if necessary.

As a guideline for the gluing of surfaces, 1 pack of TISSEEL Lyo 2 ml (i.e. 1 ml Sealer Protein Solution plus 1 ml Thrombin Solution) will be sufficient for an area of at least 10 cm². When TISSEEL Lyo is applied by spraying, the same quantity will be sufficient to coat considerably larger areas, depending on the specific indication and the individual case. When TISSEEL Lyo is used for mesh fixation it may be applied as drops and/or by a spray technique depending on the preference of the surgeon. Usually the drops of Tisseel are applied where surgeons routinely position staples and the layer of fibrin sealant achieved with spraying allows the entire mesh to be fixed in place without shrinking and folding.

The quantity of TISSEEL Lyo required for mesh fixation depends on the mesh size selected and the recommended amount is the same for different application techniques. For example, 2 - 4 ml of reconstituted TISSEEL Lyo applied as a thin layer is suitable to adequately fix a standard size mesh of approximately 10 x 15 cm.

When using the drop technique surgeons should apply TISSEEL Lyo at key anchor points for fixing the mesh (e.g. pubic tubercle in inguinal hernia repair) and at the margins of the mesh. Application by spray, either alone or in combination with drops, should cover the mesh uniformly with a thin layer.

In inguinal hernia repair the mesh covering vascular structures and nerves can be fixed with TISSEEL Lyo alone using drops and/or spray.

Method and route of administration

For epilesional use.

Prepare the solutions as described at Section 6.6.

In order to ensure optimal safe use of TISSEEL Lyo by spray application the following recommendations should be followed:

¹    KIU = Kallidinogenase Inactivator Unit

²    One International Unit (IU) of Thrombin is defined as the activity contained in 0.0853 mg of the First International Standard for Human Thrombin or the First International Standard for Alpha Thrombin Human.

TISSEEL and DUPLOJECT are trademarks of Baxter AG. BAXTER is a trademark of BAXTER International Inc.

In open wound surgery - a pressure regulator device that delivers a maximum pressure of no more than 2.0 bar (28.5 psi) should be used.

In minimally invasive/laparoscopic procedures - a pressure regulator device that delivers a maximum pressure of no more than 1.5 bar (22 psi) and uses carbon dioxide gas only should be used.

Prior to applying TISSEEL Lyo the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices). TISSEEL Lyo should only be reconstituted and administered according to the instructions and with the devices recommended for this product (see section 6.6).

For spray application, see sections 4.4 and 6.6 for specific recommendations on the required pressure and distance from tissue per surgical procedure and length of applicator tips.

In surgical procedures that require the use of minimal volumes of fibrin sealant, it is recommended to expel and discard the first few drops of product (see Section 4.4).

4.3.    Contraindications

TISSEEL Lyo must not be applied intravascularly.

Hypersensitivity to the active substances or to any of the excipients (see also section 4.4. Warnings).

TISSEEL Lyo alone is not indicated for the treatment of active or spurting arterial or venous bleeding which is not controlled by conventional surgical techniques.

4.4.    Special warnings and precautions for use

For epilesional use only. Do not apply intravascularly. Soft tissue injection of TISSEEL Lyo carries the risk of an anaphylactoid reaction and / or local tissue damage.

In surgical applications that require the use of minimal volumes of fibrin sealant (e.g. pterygium surgery) the first few drops should be expelled and discarded before application to ensure adequate mixing of the sealer protein and thrombin solutions.

Use of the first few drops in these procedures could result in the product being ineffective.

In two retrospective, non-randomized studies in Coronary Artery Bypass Graft (CABG) surgery, patients that received fibrin sealant showed a statistically significant increased risk of mortality. While these studies could not provide a determination of a causal relationship the increased risk associated with the use of TISSEEL Lyo in these patients cannot be excluded. Therefore, additional care should be taken to avoid inadvertent intravascular administration of this product.

Injection of Sealer Protein Solution and/or Thrombin Solution carries a risk of anaphylactoid reactions. Intravascular and intraventricular administration carries the additional risk of a thromboembolic complication. Both complications may be life-threatening. Therefore, care should be taken to ensure that TISSEEL Lyo and/or Thrombin Solution are only applied topically.

Any application of pressurized gas is associated with a potential risk of air or gas embolism, tissue rupture, or gas entrapment with compression, which may be life-threatening.

Apply TISSEEL Lyo as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and the wound healing process.

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 pressures 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 TISSEEL Lyo when sprayed in open wound surgery.

When applying TISSEEL Lyo using a spray device, be sure to use a pressure within the pressure range recommended by the spray device manufacturer (see table in section 6.6 for pressures and distances!.

TISSEEL Lyo spray application should only be used if it is possible to accurately judge the spray distance as recommended by the manufacturer. Do not spray closer than the recommended distances.

When spraying TISSEEL Lyo, 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 (also see section 4.2!.

As with any protein product, allergic type hypersensitivity reactions are possible. Signs of hypersensitivity reactions include hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the administration has to be discontinued immediately.

TISSEEL Lyo contains synthetic aprotinin. Even in the case of strict local application there is a risk of anaphylactic reaction, linked to the presence of aprotinin. The risk seems higher in case of previous exposure even if it was well tolerated. Therefore, any use of aprotinin, or aprotinin-containing products, should be recorded in the patients’ records.

As synthetic aprotinin is structurally identical to bovine aprotinin the use of TISSEEL in patients with allergies to bovine proteins should be carefully evaluated.

In case of shock, standard medical treatment for shock should be implemented.

Sealer Protein Solution and Thrombin Solution are made from human plasma. 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 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 erythropoiesis (e.g. haemolytic anemia).

It is strongly recommended that every time a patient receives a dose of TISSEEL Lyo, the name and batch number of the product are recorded in order to maintain a record of the batches used.

Adequate data are not available to support the use of this product in application through a flexible endoscope for treatment of bleeding or in vascular surgery.

4.5.    Interactions with other medicinal products and other forms of interaction

No formal interaction studies have been performed. Similar to comparable products or thrombin solutions, the product may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed to the greatest possible extent before applying the product.

4.6.    Pregnancy and lactation

The safety of fibrin sealants / haemostatics for use in human pregnancy or breastfeeding has not been established in controlled clinical trials. Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and postnatal development.

Therefore, the product should be administered to pregnant and lactating women only if clearly needed.

No undesirable effects during pregnancy and lactation have been reported.

4.7.    Effects on ability to drive and use machines

Not relevant.

4.8.    Undesirable effects

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the application site, bradycardia, bronchospasm, chills, dyspnoea, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, pruritus, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) may occur in rare cases in patients treated with fibrin sealants / haemostatics.

In isolated cases, these reactions have progressed to severe anaphylaxis. Such reactions may especially be seen, if the preparation is applied repeatedly, or administered to patients known to be hypersensitive to aprotinin (see Section 4.4) or any other constituents of the product.

Even if a second treatment with TISSEEL Lyo was well tolerated, a subsequent administration of TISSEEL Lyo or systemic administration of aprotinin may result in severe anaphylactic reactions.

In the event of hypersensitivity reactions the administration has to be discontinued immediately.

Soft tissue injection of TISSEEL Lyo carries the risk of an anaphylactoid reaction and / or local tissue damage (see Section 4.4).

Reactions to antibodies against components of fibrin sealant / haemostatic products may occur rarely.

Inadvertent intravascular injection could lead to thromboembolic events and disseminated intravascular coagulation, and there is also a risk of anaphylactic reaction (see Section 4.4). For safety with respect to transmissible agents, see Section 4.4.

The undesirable effects reported in the listing hereafter are based on post-market experience for this type of product. Their frequency has been evaluated by using the following criteria: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), and very rare (<1/10,000).

The undesirable effects listed below reflect the type of undesirable effects that have been reported with TISSEEL Lyo.

Their incidence rate is <1/10,000, i.e. very rare.

Cardiac disorders

•    Bradycardia, Tachycardia Gastrointestinal disorders

•    Nausea

General disorders and administration site disorders

•    Hypersensitivity reactions Immune system disorders

•    Anaphylactic reactions, Allergic reactions, Anaphylactic shock, Urticaria Injury, poisoning and procedural complications

•    Anaphylactoid reactions Investigations

•    Drop in blood pressure

Respiratory, thoracic and mediastenal disorders

•    Dyspnoea

Skin and subcutaneous tissue disorders

•    Pruritus Vascular disorders

•    Flush, (severe) Hypotension, Thromboembolic complication

4.9.    Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Pharmacotherapeutic group: local haemostatics, ATC code: B02BC; tissue adhesives, ATC code: V03A K

The fibrin adhesion system initiates the last phase of physiological blood coagulation. Conversion of fibrinogen into fibrin occurs by the splitting of fibrinogen into fibrin monomers and fibrinopeptides. The fibrin monomers aggregate and form a fibrin clot. Factor XIIIa, which is activated from factor XIII by thrombin, crosslinks fibrin. Calcium ions are required for both, the conversion of fibrinogen and the crosslinkage of fibrin.

As wound healing progresses, increased fibrinolytic activity is induced by plasmin and decomposition of fibrin to fibrin-degradation products is initiated. Proteolytic degradation of fibrin is inhibited by antifibrinolytics. Aprotinin is present in TISSEEL Lyo as an antifibrinolytic. Efficacy in haemostasis has been demonstrated in cardiopulmonary surgery, splenic surgery and neurosurgery.

Use as tissue glue to promote adhesion/sealing or as suture support: Efficacy has been demonstrated in surgeries including gastrointestinal anastomoses and neurosurgical procedures where contact with cerebro-spinal fluid or dura mater can occur.

Clinical studies demonstrating haemostasis, sealing, and tissue adhesion were conducted in at least 4,706 patients. These studies were performed in a multitude of surgical specialties, surgical procedures and applications techniques, including but not limited to haemostasis (n = 1300), gastrointestinal anastomoses (n = 1,114), neurosurgery (n = 511).

21 open and comparative clinical studies have also been conducted in 2625 patients to demonstrate the use of TISSEEL in mesh fixation during inguinal, femoral and incisional hernia repair by various open and laparoscopic techniques. TISSEEL was at least as effective as staples, tacks or sutures in mesh fixation during the repair of inguinal or femoral hernia using all the currently favoured surgical techniques. TISSEEL was at least as effective in repair of incisional hernias when judged by recurrence rates. In addition, the evidence demonstrated that there were no differences in postoperative complications between mesh fixation methods. In several studies the level of postoperative pain was significantly lower in the TISSEEL group.

There is limited experience in children during cardiac surgery (age 4 - 134 months: n = 14). Efficacy has been demonstrated also in fully heparinized patients.

5.2.    Pharmacokinetic properties

TISSEEL Lyo is intended for epilesional use only. As a consequence, intravascular pharmacokinetic studies were not performed in man.

Fibrin sealants / haemostatics are metabolized in the same way as endogenous fibrin by fibrinolysis and phagocytosis.

5.3.    Preclinical safety data

No preclinical safety data are available for TISSEEL Lyo on acute toxicity, subacute and chronic toxicity, carcinogenicity or immune stimulation. None of the proteins contained in TISSEEL Lyo, nor calcium chloride have mutagenic effects.

Animal studies in rats have not shown any local toxicity.

High doses of aprotinin injected intravenously to pregnant rats had no embryotoxic or teratogenic effect.

6. PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

6.1.1.    Excipients of Sealer Protein Concentrate Lyophilized

Human Albumin L-Histidine Niacinamide Polysorbate 80 Sodium Citrate Dihydrate Water for Injections

6.1.2.    Excipients of the Aprotinin Solution

Water for Injections

6.1.3.    Excipients of Human Thrombin Lyophilized

Human Albumin Sodium Chloride

6.1.4.    Excipients of the Calcium Chloride Solution

Water for Injections

6.2.    Incompatibilities

Sealer Protein and Thrombin Solutions can be denatured following contact with solutions containing alcohol, iodine or heavy metals. TISSEEL must not be mixed with other medicinal products.

6.3.    Shelf life

TISSEEL Lyo has a shelf life of 2 years. Do not use after the expiry date.

Chemical and physical in-use stability of reconstituted Sealer Protein and Thrombin Solutions has been demonstrated for 6 hours at room temperature up to 37°C (reconstituted product must not be returned to the refrigerator).

From a microbiological point of view the product should be used immediately, unless the method of reconstitution precludes the risk of microbial contamination. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4.    Special precautions for storage

Store at +2°C to +25°C (either in the refrigerator at +2°C to 8°C or at controlled room temperature (no exceeding +25°C). Do not freeze.

Store in the original container to protect from light.

6.5.    Nature and contents of container

All components are filled into glass containers conforming to EP requirements. The vials containing Sealer Protein Concentrate are equipped with a magnetic spin propeller.

TISSEEL Lyo is available in presentations of 2 ml, 4 ml and 10 ml.

Each TISSEEL Lyo Kit contains the following:

-    1 vial containing Sealer Protein Concentrate Lyophilized;

-    1 vial containing Human Thrombin Lyophilized;

-    1 vial containing synthetic Aprotinin Solution;

-    1 vial containing Calcium Chloride Solution;

-    1 kit for reconstitution and application 6.5.1. Kit for Reconstitution and Application

Each kit contains one single-sterile set of devices for reconstitution under non-sterile conditions, and one double-sterile set of devices for application under sterile conditions.

The set for reconstitution includes 2 disposable needles plus one blue-scaled disposable syringe and one black-scaled disposable syringe.

The set for application includes 2 disposable needles plus one blue-scaled disposable syringe and one black-scaled disposable syringe, one DUPLOJECT Two-Syringe Clip, 2 Joining Pieces and 4 Application Needles.

For details on reconstitution and application see the following section.

The sets of devices are sterile and non-pyrogenic in unopened and undamaged packages. Sterilised by exposure to ethylene oxide.

For single use only. Do not re-sterilise.

CE 0297

6.6.    Instructions for use and handling and disposal General

Before administration of TISSEEL Lyo care is to be taken that parts of the body outside the desired application area are sufficiently covered to prevent tissue adhesion at undesired sites.

To prevent TISSEEL Lyo from adhering to gloves and instruments, wet these with saline before contact.

Preparation and reconstitution

Prior to reconstitution of the fibrin sealant components the rubber stoppers of all vials should be cleansed. Direct contact of disinfectant and product must be avoided (see Section 4.5).

I.    Preparation of Sealer Protein Solution (First Component)

Sealer Protein Concentrate Lyophilized is dissolved with the Aprotinin Solution to form Sealer Protein Solution.

Sealer Protein Concentrate Lyophilized is reconstituted using the FIBRINOTHERM warming and stirring device (recommended method). Alternatively, a sterile water bath at a temperature of 33 - 37°C can be used.

Reconstitution using the FIBRINOTHERM device:

The FIBRINOTHERM device maintains a constant temperature of 37°C. It also shortens the dissolution time of the Sealer Protein Concentrate Lyophilized by rotating the magnetic stirrer contained in each Sealer Protein Concentrate Lyophilized vial.

-    Place the vials containing Sealer Protein Concentrate Lyophilized and Aprotinin Solution into the appropriate openings of the FIBRINOTHERM device and preheat the vials for approximately 3 minutes.

-    Transfer the Aprotinin Solution into the vial containing the Sealer Protein Concentrate Lyophilized using one needle and the blue-scaled syringe provided in the single-sterile kit for reconstitution. Place the Sealer Protein Concentrate Lyophilized vial into the stirring well of the FIBRINOTHERM device (use the appropriate adaptor, if necessary) and stir until complete dissolution. Reconstitution is complete as soon as no particles are visible anymore when holding the vial against the light. If particles are present, keep on stirring the solution at 37°C for a few more minutes until complete dissolution. Turn off the magnetic stirrer when dissolution is complete.

Note: Excessive stirring might compromise product quality

-    Keep the Sealer Protein Solution at 37°C without stirring if it is not used immediately. To ensure homogeneity stir or swirl briefly before drawing up the Sealer Protein Solution into the blue-scaled syringe provided in the double sterile kit for application.

-    Withdraw the reconstituted Sealer Protein Solution from the vial under sterile conditions. For further instructions please refer to the instructions for use of the FIBRINOTHERM device. Reconstitution using a water bath:

-    Preheat the vials containing the Sealer Protein Concentrate Lyophilized and the Aprotinin Solution for approximately 3 minutes in a water bath at a temperature of 33 - 37°C. (Heating beyond 37°C must be avoided)

-    Transfer the Aprotinin Solution into the vial containing the Sealer Protein Concentrate Lyophilized using one needle and the blue-scaled syringe provided in the single-sterile kit for reconstitution.

-    Return the Sealer Protein Concentrate Lyophilized vial to the water bath at 33 - 37°C for one minute.

-    Swirl briefly but avoid excessive frothing. Then return the vial to the water bath and check periodically for complete dissolution. Reconstitution is complete as soon as no particles are visible when holding the vial against the light. If particles are present keep the vial at 33 - 37°C for a few more minutes and agitate the solution until complete dissolution.

-    Keep the Sealer Protein Solution at 33 - 37°C after complete dissolution if it is not used immediately. To ensure homogeneity swirl briefly before drawing up the solution into the blue-scaled syringe provided in the double sterile kit for application.

-    Withdraw the reconstituted Sealer Protein Solution from the vial under sterile conditions. Note: When using a water bath for reconstitution instead of the FIBRINOTHERM device,

special precautions have to be taken against submersing the vial, particularly the septum, to avoid possible contamination.

II.    Preparation of Thrombin Solution (Second Component)

The Human Thrombin Lyophilized is dissolved with the Calcium Chloride Solution to form the Thrombin Solution. Transfer the contents of the Calcium Chloride Solution vial into the Thrombin vial. Use the second needle and the black-scaled syringe provided in the singlesterile kit for reconstitution.

Swirl briefly to dissolve the lyophilized material. To warm the Thrombin Solution either the FIBRINOTHERM device or a water bath can be used. Keep the Thrombin Solution at 33 - 37°C until used. Prior to use draw up the Thrombin Solution from the vial using the second needle and the black-scaled syringe provided in the double-sterile kit for application. Note: Syringes and needles used for the reconstitution of one component must not be re-used for the reconstitution of the other component, as this would lead to solidification of that component in the vial or syringe.

III.    Use of reconstituted Fibrin Sealant Components

Both fibrin sealant components must be used within 6 hours after reconstitution. Administration

The Sealer Protein and the Thrombin Solutions should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discoloration prior to administration.

Prior to administration, TISSEEL Lyo should be warmed to 33 - 37°C.

For application the two single-use syringes with the reconstituted Sealer Protein Solution and Thrombin Solution have to be clipped into the DUPLOJECT Two-Syringe Clip and this assembly has to be connected to a joining piece and an application needle. All necessary devices are provided in the double-sterile kit for application.

The common plunger of the DUPLOJECT Two-Syringe Clip ensures that equal volumes are fed through the joining piece before being mixed in the application needle and ejected.

Operating Instructions

-    Place the two syringes filled with Sealer Protein Solution and with Thrombin Solution into the clip. Both syringes should be filled with equal volumes.

-    Connect the nozzles of the two syringes to the joining piece ensuring that they are firmly fixed. Secure the joining piece by fastening the tether strap to the DUPLOJECT Two-Syringe Clip. Should the pull strap tear, use the spare joining piece. If none is available, further use is still possible but tightness of the connection needs to be ensured to prevent any risk of leaking.

-    Fit an application needle onto the joining piece.

Do not expel the air remaining inside the joining piece or application needle until you start actual application as the aperture of the needle may clog otherwise.

-    Apply the mixed Sealer Protein-Thrombin Solution onto the recipient surface or surfaces of the parts to be sealed.

For surgical procedures that require minimal volumes of fibrin sealant do not use the first few drops of TISSEEL Lyo (see Sections 4.2 and 4.4)

If application of the fibrin sealant components is interrupted, clogging occurs immediately in the needle. Replace the application needle with a new one only immediately before application is resumed. If the apertures of the joining piece are clogged, use the spare joining piece provided in the package.

Note: After blending of the sealant components, the fibrin sealant starts to set within seconds on account of the high Thrombin concentration (500 IU/ml).

Application is also possible with other accessories supplied by BAXTER that are particularly suited for, e.g., minimally invasive surgery, application to large or difficult-to-access areas. When using these application devices, strictly follow the Instructions for Use of the devices.

After the two components have been applied, approximate the wound areas. Fix or hold the glued parts with continuous gentle pressure in the desired position for about 3 - 5 minutes to ensure that the setting fibrin sealant adheres firmly to the surrounding tissue.

In certain applications biocompatible material, such as collagen fleece, is used as a carrier substance or for reinforcement.

Spray application

When applying TISSEEL Lyo using a spray device be sure to use a pressure and a distance from tissue within the ranges recommended by the manufacturer as follows:

Recommended pressure. distance and devices for spray application of TISSEEL Lyo
Surgery	Spray set to be used	Applicator tips to be used	Pressure regulator to be used	Recommended distance from target tissue	Recom mended spray pressure
Open wound	Tisseel / Artiss Spray Set	n.a.	EasySpray	10 - 15 cm	1.5 - 2.0 bar (21.5 -28.5 psi)
	Tisseel / Artiss Spray Set 10 pack	n.a.	EasySpray
Laparo- scopic/ minimally invasive procedures	n.a.	Duplospray MIS Applicator 20 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11	2 - 5 cm	1.2 - 1.5 bar (18 - 22 psi)
		Duplospray MIS Applicator 30 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Duplospray MIS Applicator 40 cm	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11
		Replaceable tip	Duplospray MIS Regulator Duplospray MIS Regulator NIST B11

When snrayinn the TISSEEL Lvo. 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 (see sections 4.2 and 4.41.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7.    MARKETING AUTHORISATION HOLDER

Baxter Healthcare Ltd.,

Caxton Way,

Thetford, Norfolk, UK,

IP24 3SE.

8.    MARKETING AUTHORISATION NUMBER(S)

PL 00116/0321

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31^s1 May 2000 / 24^lh March 2006

10.    DATE OF REVISION OF TEXT

15 March 2013

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