Tissil Lio (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Baxter Medical Products, GmbH (Austria)

Manufactured By

Baxter, AG (Austria)

Or

Siegfried Hameln, GmbH (Germany)

Packaging and Quality Control Release

BAXTER, AG (Austria)

ATC Code

B02BC30 (Local hemostatics in combinations)

Active Substances

Fibrinogen (Rec.INN registered by WHO)

Thrombin (Rec.INN registered by WHO)

Dosage Form

Tissil Lio

Lyophilisate for the preparation of solution for topical application 45.5 mg/ml+250 IU/ml: vial

Dosage Form, Packaging, and Composition

Set of lyophilisates for the preparation of solution for topical application

2 ml – vials (2 pcs.) – cardboard packs – “sleeve” type packages /in set: protein glue concentrate (vials), synthetic aprotinin solution (vials) – 1 ml, Thrombin (vials) and calcium chloride solution (vials) – 1 ml; applicator set “Duploject System”: double cassette for syringes with plunger – 1 pc., connecting units – 2 pcs., disposable syringes with black marking – 2 pcs., disposable syringes with blue marking – 2 pcs., disposable needles – 4 pcs., applicator cannulas – 4 pcs./ – By prescription
4 ml – vials (2 pcs.) – cardboard packs – “sleeve” type packages /in set: protein glue concentrate (vials), synthetic aprotinin solution (vials) – 2 ml, Thrombin (vials) and calcium chloride solution (vials) – 2 ml; applicator set “Duploject System”: double cassette for syringes with plunger – 1 pc., connecting units – 2 pcs., disposable syringes with black marking – 2 pcs., disposable syringes with blue marking – 2 pcs., disposable needles – 4 pcs., applicator cannulas – 4 pcs./ – By prescription
10 ml – vials (2 pcs.) – cardboard packs – “sleeve” type packages /in set: protein glue concentrate (vials), synthetic aprotinin solution (vials) – 5 ml, Thrombin (vials) and calcium chloride solution (vials) – 5 ml; applicator set “Duploject System”: double cassette for syringes with plunger – 1 pc., connecting units – 2 pcs., disposable syringes with black marking – 2 pcs., disposable syringes with blue marking – 2 pcs., disposable needles – 4 pcs., applicator cannulas – 4 pcs./ – By prescription

Clinical-Pharmacological Group

Hemostatic agent for topical application

Pharmacotherapeutic Group

Local hemostatics in combination

Indications

• Hemostasis: As an adjunct to hemostasis in surgeries involving cardiopulmonary bypass, treatment of parenchymal tissue (e.g., liver, spleen), and other procedures where control of bleeding by conventional surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.
• Sealing: For the sealing of colostomies. As a sealant for the prevention of postoperative alveolar-pleural fistulas and air leaks following pulmonary surgery. For the fixation of autologous skin grafts and hemostasis in burn patients, particularly where the grafted area is excised to the subcutaneous fat layer or deeper.
• Support for Anastomoses: As a supporting agent for the closure of colonic anastomoses to reduce the incidence of anastomotic leakage.
• Fibrin Glue Application: The product is intended for use as a fibrin glue, where the combination of fibrinogen and thrombin replicates the final stage of the coagulation cascade, forming a stable fibrin clot at the site of application.

The application of Tissil Lio is always performed by a qualified surgeon and is contingent upon the specific surgical situation and the surgeon’s professional judgment regarding the necessity for an adjunctive hemostatic or sealing agent.

Contraindications

• Hypersensitivity: Known hypersensitivity to any component of the formulation, including bovine-derived aprotinin or other constituents. A thorough patient history should be taken to rule out potential allergic reactions.
• Intravascular Application: The product is strictly contraindicated for intravascular injection. Introduction into blood vessels can lead to widespread, potentially life-threatening thrombosis, including catastrophic events such as stroke, myocardial infarction, or pulmonary embolism.
• Application Sites: Do not apply into large open vessels, infected wounds, or areas with active, untreated infection. Application in such sites may impair healing, promote infection spread, or lead to embolization of the fibrin clot.
• Neurosurgical Use: Contraindicated for use on skin incision sites or for dural closure in neurosurgical procedures due to the potential risk of compression and associated neurological damage.
• Specific Patient Populations: The safety and efficacy of Tissil Lio have not been established in pediatric populations, and its use is therefore contraindicated in children. Use during pregnancy or lactation is also contraindicated unless the potential benefit to the mother clearly outweighs the potential risk to the fetus or infant, due to a lack of adequate and well-controlled studies.

Dosage Regimen

The dosage of Tissil Lio is highly individualized and depends entirely on the size of the area to be treated and the specific surgical indication (hemostasis vs. sealing). The goal is to apply the minimum amount necessary to achieve the desired clinical effect.

The product is prepared immediately before use by reconstituting the lyophilized components with the provided solvents. The fibrinogen component is reconstituted with the supplied synthetic aprotinin solution, and the thrombin component is reconstituted with the supplied calcium chloride solution. The two solutions are then loaded into the separate syringes of the Duploject applicator system.

For application, the two components are mixed at the target site via the applicator, forming the fibrin glue. A thin, even layer is typically sufficient. For hemostasis, the product is applied directly to the bleeding surface. For sealing, it is applied to the surfaces to be joined before they are approximated and held in place for approximately 3-5 minutes to allow for complete clot formation and adhesion.

The surgeon must assess the adequacy of the application and may reapply if necessary. There is no standard dosage in milliliters or milligrams; the quantity used is determined by the surgeon’s visual assessment of the operative field. The available pack sizes (2 ml, 4 ml, 10 ml) allow for selection based on the anticipated need for the procedure.

Adverse Reactions

Adverse reactions to Tissil Lio are relatively uncommon but can occur. The most frequently reported reactions are related to hypersensitivity or the surgical procedure itself.

Allergic Reactions: These can range from mild localized reactions (such as rash, pruritus, or erythema) to severe systemic reactions, including anaphylaxis. The risk is heightened in patients with known sensitivity to bovine proteins (due to aprotinin) or other components. Preoperative inquiry about known allergies is essential.

Thromboembolic Events: Although the product is for topical use, there is a theoretical risk of thromboembolic complications if the material inadvertently enters the systemic circulation or if it is applied in a manner that could lead to the obstruction of blood flow. This includes events like deep vein thrombosis, pulmonary embolism, or arterial thrombosis.

Inflammatory Reactions: As with any foreign protein application, there is a potential for localized inflammatory responses, including fever, pain, swelling, or delayed healing at the application site. These are generally transient and self-limiting.

Infection: As the product is derived from human plasma, the theoretical risk of transmitting infectious agents cannot be completely excluded, despite rigorous donor screening and manufacturing processes that include viral inactivation and removal steps. Signs of infection at the surgical site should be monitored.

Any adverse reaction suspected to be associated with Tissil Lio should be reported to the appropriate health authority and the marketing authorization holder.

Drug Interactions

Formal drug interaction studies have not been conducted with Tissil Lio. However, pharmacological considerations suggest potential interactions with other agents affecting coagulation.

Anticoagulants: The hemostatic effect of Tissil Lio may be antagonized by systemic anticoagulant therapy, such as with heparin, warfarin, or direct oral anticoagulants (DOACs). The efficacy of the fibrin sealant could be reduced in patients receiving these medications.

Anti-fibrinolytic Agents: The presence of aprotinin (an anti-fibrinolytic agent) in the formulation is intended to stabilize the fibrin clot. Concurrent use with other systemic anti-fibrinolytic drugs (e.g., tranexamic acid, aminocaproic acid) could theoretically potentiate the thrombogenic effect, although this risk is considered low with topical application.

Platelet Inhibitors: Drugs that inhibit platelet aggregation, such as aspirin, clopidogrel, or other P2Y12 inhibitors, may also impair the overall hemostatic process and potentially reduce the adjunctive efficacy of Tissil Lio in achieving hemostasis, as platelet plug formation is a complementary mechanism to fibrin clot formation.

It is critical to inform the surgical team of all medications the patient is taking, particularly those affecting hemostasis, to allow for appropriate perioperative management and risk assessment.

Overdose

Overdose with Tissil Lio in the conventional sense is unlikely due to its topical application and localized action. The primary risk associated with excessive application is not systemic toxicity but rather local complications.

Local Mass Effect: Applying an excessive volume of the fibrin glue can lead to the formation of a large, space-occupying clot. This can cause mechanical compression on adjacent tissues or neural structures, potentially leading to ischemia, nerve damage, or compromised organ function. In confined anatomical spaces, such as in neurosurgery or ophthalmology, even a small excess can be significant.

Foreign Body Reaction: An unusually large amount of fibrin-based material may provoke a more pronounced foreign body reaction, potentially leading to increased inflammation, granuloma formation, or fibrosis, which could interfere with normal tissue healing and repair.

Thromboembolic Risk: While the risk is low with correct topical application, the inadvertent introduction of a large amount of the product into a blood vessel would constitute a severe overdose scenario, leading to massive, life-threatening thrombosis.

There is no known antidote for an overdose of Tissil Lio. Management is entirely supportive and involves surgical intervention if necessary to remove excess material causing compression. The cornerstone of prevention is the application of the smallest effective amount by a trained surgeon.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.