Tachocomb

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TACHOCOMB (TachoComb®)

Composition:

Active substances:
human thrombin, human fibrinogen;

1 cm² of the matrix contains 2.0 IU of human thrombin and 5.5 mg of human fibrinogen;

Excipients:
collagen (from equine tendon), riboflavin E 101.

Pharmaceutical form.
Matrix for tissue sealing.

Main physicochemical characteristics:
white plate with a yellow coating on one side.

Pharmacotherapeutic group.
Hemostatic agents for local use.

ATC code B02BC30.

Pharmacological Properties

Pharmacodynamics

TAHOCOMB contains fibrinogen and thrombin as a dry coating on the surface of a collagen matrix. Upon contact with physiological fluids such as blood, lymph, or physiological saline, the coating components dissolve and partially diffuse into the wound surface. This is followed by the fibrinogen-thrombin reaction, which initiates the final phase of physiological blood coagulation. Fibrinogen is converted into fibrin monomers, which spontaneously polymerize into a fibrin clot that firmly holds the collagen sheet on the wound surface. Subsequently, fibrin forms cross-links with endogenous factor XIII, creating a strong, mechanically stable mesh with high adhesive properties, thus also providing tissue sealing.

Clinical studies demonstrating hemostasis have been conducted overall in 240 patients (119 patients received TAHOCOMB, 121 received argon plasma coagulation) undergoing partial liver resection, and in 185 patients (92 patients received TAHOCOMB, 93 patients received standard surgical treatment) undergoing surgical resection of superficial renal tumors. In another controlled study involving 119 patients (62 patients received TAHOCOMB, 57 patients received a hemostatic patch), tissue sealing, presence of hemostasis, and suture support were demonstrated in patients undergoing cardiovascular surgery. Tissue sealing during lung surgery was evaluated in two controlled studies in patients who underwent lung surgery. In the first controlled clinical trial assessing tissue sealing in lung surgery, superiority of the product over standard treatment could not be demonstrated based on air leak assessment, due to inclusion of a large group of patients (53%) without air leakage. However, in the second study, which evaluated tissue sealing in 299 patients (149 patients received TAHOCOMB, 150 patients received standard surgical treatment), and which included patients with intraoperative air leakage, superiority of TAHOCOMB over standard treatment was demonstrated.

The efficacy of TAHOCOMB as an adjunct to suture closure of the dura mater was evaluated in a randomized, controlled study in 726 patients (362 patients were randomized to the TAHOCOMB group, 364 patients to the control group) undergoing cranial base surgery. Efficacy was assessed postoperatively by recording confirmed cerebrospinal fluid leakage, development of pseudomeningocele, or intraoperative inefficacy. In this trial, superiority of the investigational product over current practice (including use of suture material, dural grafting, and application of fibrin, polymeric sealants, or their combination) could not be confirmed. The number of patients with an efficacy event was 25 (6.9%) and 30 (8.2%) in the TAHOCOMB group and the current practice group, respectively, corresponding to an odds ratio of 0.82 (95% CI: 0.47; 1.43). However, the results of the odds ratio assessment with 95% confidence intervals indicate that the efficacy of TAHOCOMB is similar to that of current practice. In this study, two application techniques of TAHOCOMB were evaluated: application of TAHOCOMB on the outer side of the dura mater and application on both sides of the dura mater. The results did not confirm superiority of the second method. When used as an adjunct for closure of the dura mater in neurosurgical procedures, TAHOCOMB demonstrated good tolerability and safety.

Pharmacokinetics

TAHOCOMB is intended solely for local application to the affected site. Intravascular administration is contraindicated. Therefore, pharmacokinetic studies following intravascular administration in humans have not been conducted.

Fibrin sealants/hemostatic agents are metabolized similarly to endogenous fibrin, through fibrinolysis and phagocytosis processes.

Animal study results indicate that after application to the wound surface, TAHOCOMB undergoes biodegradation with minimal residual material remaining at 13 weeks. Complete degradation of the product was observed in some animals at 12 months after application to the liver wound surface, while in others, a small amount of residual material was still detectable. Degradation is associated with granulocyte infiltration and formation of resorptive granulation tissue with encapsulation of degraded TAHOCOMB remnants. During animal studies, no signs of local intolerance to the product were observed.

In clinical experience with human use, isolated cases have been reported where residual material was observed without any signs of functional impairment.

Clinical characteristics.

Indications.

The product is indicated as supportive therapy in adult patients to improve haemostasis and tissue bonding during surgical procedures, to secure surgical sutures in vascular surgery when standard techniques are insufficient, and to secure dural sutures to prevent postoperative cerebrospinal fluid leakage following neurosurgical procedures.

Contraindications.

Do not administer intravascularly.

Hypersensitivity to the components of the matrix.

Interaction with other medicinal products and other forms of interaction.

Official studies on interactions with other medicinal products have not been conducted.

Similar to comparable medicinal products or thrombin solutions, TACHOCOMB may be denatured by solutions containing alcohol, iodine, or heavy metals (e.g., antiseptic solutions). Such substances should be removed to the greatest extent possible prior to application of the product.

Special precautions for use.

For topical application only in surgical procedures. Do not use intravascularly.

If administered intravascularly, the product may cause life-threatening thromboembolic complications.

Specific data on the use of the product in gastrointestinal anastomoses are not available.

It is unknown whether recent radiotherapy affects the efficacy of TACHOCOMB when used for suture reinforcement of the dura mater.

As with any protein-containing products, hypersensitivity reactions of the allergic type may occur during the use of TACHOCOMBO. Signs of hypersensitivity reactions include rash, generalized urticaria, chest tightness, stridor, arterial hypotension, and anaphylaxis. If any of these symptoms occur, administration of the product must be discontinued immediately.

To prevent adhesion formation in tissues at unintended sites, ensure that tissues outside the intended area of application are adequately protected prior to applying TACHOCOMB (see section "Instructions for use and dosage"). Cases of tissue adhesion in the gastrointestinal tract have been reported following use in abdominal surgery when surgical procedures were performed in close proximity to the intestine, leading to gastrointestinal obstruction.

Standard medical treatment for anaphylactic shock should be followed if such a condition occurs.

Standard measures to prevent infections from medicinal products derived from human blood or plasma include donor selection, screening of individual donor blood and plasma pools for specific infection markers, and inclusion of effective viral inactivation/removal steps in the manufacturing process. Nevertheless, when using medicinal products derived from human blood or plasma, transmission of infectious agents cannot be completely ruled out, including unknown or emerging viruses and other pathogens.

Measures for preventing infections are considered effective against enveloped viruses such as HIV, hepatitis B virus, and hepatitis C virus, as well as against non-enveloped viruses like hepatitis A virus. However, these measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may have serious consequences for pregnant women (intrauterine infection) and individuals with immunodeficiency or increased erythropoiesis (e.g., hemolytic anemia).

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly documented.

Use during pregnancy or breastfeeding.

The safety of TACHOCOMB in pregnant or breastfeeding women has not been established in controlled clinical trials.

There is insufficient preclinical data on the assessment of the product's safety on reproductive function, embryonic or fetal development, course of pregnancy, and peri- and postnatal development. Therefore, TACHOCOMB should be used during pregnancy or breastfeeding only if clearly needed.

Effect on ability to drive and operate machinery.
None.

Method of Administration and Dosage.

For local topical application in surgery. Do not administer intravascularly. TACHOCOMF should be applied only by experienced surgeons.

The number of TACHOCOMF pads applied should correspond to the clinical needs of the patient and the size of the wound surface, and must be determined individually by the surgeon. In clinical studies, individual doses typically consisted of 1–3 pads (9.5 cm × 4.8 cm); application of up to 10 units has been reported. For smaller wounds, such as those in minimally invasive surgical procedures, it is recommended to use a smaller-sized pad (4.8 cm × 4.8 cm or 2.5 cm × 3.0 cm) or a pre-rolled pad (based on the 4.8 cm × 4.8 cm pad).

TACHOCOMF is supplied as a ready-to-use product in a sterile package and should be handled accordingly. Only undamaged packages should be used. Re-sterilization after opening the package is not possible. The outer aluminum foil packaging may be opened in a non-sterile working area. The inner sterile blister must be opened in a sterile operating room environment. TACHOCOMF should be applied immediately after opening the inner sterile packaging.

The product must be used under sterile conditions. Prior to pad application, the wound surface should be cleaned (e.g., from blood, disinfectants, and other fluids).

After removing the TACHOCOMF pad from its sterile packaging, it should be pre-moistened with physiological saline solution and then immediately applied. The active side of the pad, marked in yellow, should be placed directly onto the bleeding wound surface or the surface with oozing blood, and gently pressed for 3–5 minutes. This procedure allows for easy adhesion of the TACHOCOMF pad to the wound surface.

After removing the pre-rolled TACHOCOMF pad from its sterile packaging, it should be immediately applied through a trocar without prior moistening. During unrolling, the yellow active side should be applied to the bleeding surface or the surface with oozing blood, using, for example, a clean forceps, while gently pressing with a moistened sponge for 3–5 minutes. This procedure facilitates the easy adhesion of TACHOCOMF to the wound surface.

Pressure should be applied using moistened surgical gloves worn during the procedure or a moistened sponge. Due to the high affinity of collagen to blood, TACHOCOMF may also adhere to surgical instruments, gloves, or adjacent tissues covered with blood. This can be avoided by cleaning surgical instruments, gloves, and adjacent tissues prior to pad application. Inadequate cleaning of adjacent tissues may lead to adhesion formation (see section "Special Warnings and Precautions for Use"). After pressing the pad onto the wound, the glove or sponge should be carefully removed. To prevent displacement of the pad, it may be held in place at one edge, for example, with a forceps.

As an alternative, for example, in cases of severe bleeding, TACHOCOMF may be applied without prior moistening, by gently pressing the pad onto the wound for 3–5 minutes.

The active side of the TACHOCOMF should be applied so that it extends 1–2 cm beyond the wound edge. When more than one pad is used, they should overlap. If necessary, the pad may also be cut to achieve the desired size and shape.

In neurosurgical procedures, TACHOCOMF should be used as an adjunct to the primary method of dura mater closure.

The pre-rolled pad can be used both in open surgical procedures and in minimally invasive surgery; the product can pass through a port or trocar of 10 mm or larger.

Any unused product or waste material must be disposed of in accordance with local regulations.

Children.
As there are insufficient data on the safety and efficacy of TACHOCOMF in children, its use is not recommended in patients under 18 years of age.

Overdose.
Cases of overdose with TACHOCOMF have not been reported.

Adverse Reactions

Hypersensitivity or allergic reactions (angioneurotic edema, burning and stinging sensations at the site of application, bronchospasm, chills, flushing, generalized urticaria, headache, rash, arterial hypotension, apathy, nausea, restlessness, tachycardia, chest tightness, paresthesia, vomiting, stridor) may rarely occur in patients using fibrin sealants/hemostatic agents. In isolated cases, these reactions may progress to severe anaphylaxis. Such reactions have mainly been observed during repeated administration of the product or in cases of increased sensitivity to its components.

Immunogenicity

Antibody formation against components of fibrin sealant/hemostatic agents has been observed in rare cases.

During clinical studies involving the use of the product in liver surgery, where antibody formation was investigated, 26% of 96 tested patients who received TACHOCOMB developed antibodies against equine collagen. Antibodies against equine collagen formed in some patients after administration of TACHOCOMB did not cross-react with human collagen. In one patient, antibodies against human fibrinogen were formed.

Adverse effects caused by the formation of antibodies against human fibrinogen or equine collagen did not occur.

Clinical data on repeated administration of TACHOCOMB are limited. The product was re-administered to 2 patients during a clinical study; no immunologically mediated adverse effects were reported; however, their antibody status regarding collagen or fibrinogen is unknown.

Thromboembolic complications may occur following intravascular application of the product (see section "Special Instructions").

Data on viral safety of the product are provided in the section "Special Instructions".

Safety data for TACHOCOMB generally reflect the type of postoperative complications associated with the surgical settings in which the studies were conducted and the underlying conditions of the patients.

Data from 8 controlled clinical trials conducted by the marketing authorization holder were pooled into a single dataset. According to the pooled data analysis, TACHOCOMB was administered to 997 patients and the comparator agent to 984 patients. For practical reasons (compared to standard surgical and standard hemostatic treatments), double-blind clinical trials evaluating the use of TACHOCOMB were not feasible; therefore, open-label clinical trials were conducted.

The adverse reactions listed below were reported during post-marketing use of TACHOCOMB. Frequency of adverse reactions: not known (frequency cannot be estimated from the available data).

Immune system disorders

Not known: anaphylactic shock, hypersensitivity reactions.

Vascular disorders

Not known: thrombosis.

Gastrointestinal disorders

Not known: intestinal obstruction (during abdominal surgery).

General disorders and administration site conditions

Not known: adhesion formation.

Shelf life.
3 years.

Storage conditions.
Store at a temperature not exceeding 25 °C. Keep out of reach of children!

Packaging.
One matrix of size 2.5 cm x 3.0 cm in a blister; one blister in a pouch; one pouch in a cardboard box;

One matrix of size 4.8 cm x 4.8 cm in a blister; one blister in a pouch; two pouches in a cardboard box;

One matrix of size 9.5 cm x 4.8 cm in a blister; one blister in a pouch; one pouch in a cardboard box.

Prescription category.
Prescription only.

Manufacturer.
Corza Medical Distribution GmbH, Austria Branch, Austria / Corza Medical Distribution GmbH, Austria Branch, Austria.

Manufacturer's address and place of business.
St. Peter Strasse 25, 4020 Linz, Austria / St. Peter Strasse 25, 4020 Linz, Austria.