TISSEEL Lyo Two-Component Fibrin Sealant 2ml

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 KIU1/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 µmol/ml

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.

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:

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 Interaction 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 h

Weight	0.5 kg

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