TACHOSIL 5.5mg / 2UI matrix for local hemostasis medication leaflet

TachoSil sealant matrix

TachoSil contains per cm2:

Human fibrinogen 5.5 mg

Human thrombin 2.0 IU

For a full list of excipients, see section 6.1.

Sealant matrix.

TachoSil is an off-white sealant matrix. The active side of the matrix, which is coated with fibrinogenand thrombin, is marked by a yellow colour.

TachoSil is indicated in adults and children from 1 month of age for supportive treatment in surgeryfor improvement of haemostasis, to promote tissue sealing and for suture support in vascular surgerywhere standard techniques are insufficient.

TachoSil is indicated in adults for supportive sealing of the dura mater to prevent postoperativecerebrospinal leakage following neurological surgery (see section 5.1).

The use of TachoSil is restricted to experienced surgeons.

The quantity of TachoSil to be applied should always be oriented towards the underlying clinical needfor the patient. The quantity of TachoSil to be applied is governed by the size of the wound area.

Application of TachoSil must be individualised by the treating surgeon. In clinical studies, theindividual doses have typically ranged from 1-3 units (9.5 cm x 4.8 cm); application of up to 10 unitshas been reported. For smaller wounds, e.g., in minimally invasive surgery the smaller size matrices(4.8 cm x 4.8 cm or 3.0 cm x 2.5 cm) or the pre-rolled matrix (based on a matrix of 4.8 cm x 4.8 cm) isrecommended.

Correct product handling and application is required. Some cases of adhesion (see section 4.4) andproduct adhesion issues have been reported (see section 4.8, and section 6.6).

For epilesional use only. Do not use intravascularly.

See section 6.6 for more detailed instructions.

TachoSil must not be applied intravascularly.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

General Precautions

For epilesional use only.

Do not use intravascularly. Life threatening thromboembolic complications may occur if thepreparation is applied intravascularly.

Specific data have not been obtained on the use of this product in gastrointestinal anastomosessurgery.

It is not known whether recent radiation therapy affects the efficacy of TachoSil when used for duramater sealing.

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

Adhesions

To prevent the development of tissue adhesions at undesired sites, ensure tissue areas outside thedesired application area are adequately cleansed before administration of TachoSil (see section 6.6).

Events of adhesions to gastrointestinal tissues leading to gastrointestinal obstruction have beenreported with use in abdominal surgery carried out in proximity to the bowel.

In case of shock, the current medical standards for shock treatment should be observed.

Transmissible Agents

Standard measures to prevent infections resulting from the use of medicinal products prepared fromhuman blood or plasma include selection of donors, screening of individual donations and plasmapools for specific markers of infection and the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when medicinal products prepared from human blood orplasma are administered, the possibility of transmitting infective agents cannot be totally excluded.

This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV andfor the non-enveloped virus HAV. The measures taken may be of limited value against non-envelopedviruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetalinfection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., haemolyticanaemia).

No interaction studies have been performed.

Similar to comparable products or thrombin solutions, the sealant may be denatured after exposure tosolutions containing alcohol, iodine or heavy metals (e.g., antiseptic solutions). Such substancesshould be removed to the greatest possible extent before applying the sealant.

The safety of TachoSil for use in human pregnancy or breastfeeding has not been established incontrolled clinical studies. Experimental animal studies are insufficient to assess the safety withrespect to reproduction, development of the embryo or foetus, the course of gestation and peri- andpostnatal development.

Therefore, TachoSil should be administered to pregnant and breastfeeding women only if clearlyneeded.

Not relevant.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theapplication site, bronchospasm, chills, flushing, generalised urticaria, headache, hives, hypotension,lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) mayoccur in rare cases in patients treated with fibrin sealants/haemostatics. In isolated cases, thesereactions may progress to severe anaphylaxis. Such reactions may especially be seen, if thepreparation is applied repeatedly, or administered to patients known to be hypersensitive toconstituents of the product.

Antibodies against components of fibrin sealant/haemostatic products may occur rarely.

However, in a clinical study with TachoSil in hepatic surgery, in which patients were investigated forthe development of antibodies, 26% of the 96 patients tested and treated with TachoSil developedantibodies to equine collagen. The equine collagen antibodies that developed in some patients after

TachoSil use were not reactive with human collagen. One patient developed antibodies to humanfibrinogen.

There were no adverse events attributable to the development of human fibrinogen or equine collagenantibodies.

There is very limited clinical data available regarding re-exposure to TachoSil. Two subjects havebeen re-exposed in a clinical study and have not reported any immune-mediated adverse events;however, their antibody status to collagen or fibrinogen is unknown.

Thromboembolic complications may occur if the preparation is applied intravascularly (seesection 4.4).

Some cases of product residue, that might have caused a foreign-body reaction in the form ofgranuloma, have been reported.

For viral safety see section 4.4.

The safety data of TachoSil generally reflect the type of post-operative complications related to thesurgical settings in which the trials were conducted and the underlying disease of the patients.

Data from the eight controlled clinical studies conducted by the MAH has been pooled into anintegrated dataset. In the integrated analyses, 997 patients were treated with TachoSil, and 984 patientswere treated with comparator treatment. Due to practical reasons (comparison to standard surgical andstandard haemostatic treatment), blinding was not possible in the TachoSil trials. Therefore, thestudies were performed as open-label studies.

The following adverse reactions have been reported with TachoSil during post marketing experience.

The frequency of all of the events listed below has been categorised as not known (cannot beestimated from the available data).

System organ class Frequency not known

Immune system disorders Anaphylactic shock, Hypersensitivity

Vascular disorders Thrombosis

Gastrointestinal disorders Intestinal obstruction (in abdominal surgeries)

General disorders and administration site Adhesionsconditions Foreign-body granuloma formation

Product adhesion issue

Product non-adhesion-issues

Some cases of product non-adhesion issues have been reported in the form of lack of product adhesion/ lack of efficacy. Correct product handling and application is required (see section 4.2 and section6.6).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Local haemostatics, ATC code: B02BC30

TachoSil contains fibrinogen and thrombin as a dried coating on the surface of a collagen matrix. Incontact with physiological fluids, e.g., blood, lymph or physiological saline solution the componentsof the coating dissolve and partly diffuse into the wound surface. This is followed by thefibrinogen-thrombin reaction which initiates the last phase of physiological blood coagulation.

Fibrinogen is converted into fibrin monomers which spontaneously polymerise to a fibrin clot, whichholds the collagen matrix tightly to the wound surface. The fibrin is then cross linked by endogenousfactor XIII, creating a firm, mechanically stable network with good adhesive properties and thereforeprovides sealing as well.

Clinical studies demonstrating haemostasis were conducted in a total of 240 patients (119 TachoSil,121 argon beamer) undergoing partial liver resection surgery and 185 patients (92 TachoSil,93 standard surgical treatment) undergoing surgical resection of superficial renal tumour. A furthercontrolled study in 119 patients (62 TachoSil, 57 haemostatic fleece) demonstrated sealing,haemostasis and suture support in patients undergoing cardiovascular surgery. Tissue sealing in lungsurgery was investigated in two controlled trials in patients undergoing lung surgery. The firstcontrolled clinical study investigating tissue sealing in lung surgery failed to document superiorityover standard treatment measured by air leakage due to the inclusion of a large group of patients(53%) without air leakage. However, the second study investigating tissue sealing in 299 patients(149 TachoSil, 150 standard surgical treatment) with demonstrated intraoperative air leakage showedthe superiority of TachoSil compared to standard treatment.

The efficacy of TachoSil was tested in a randomised controlled study in 726 patients (362 treated with

TachoSil and 364 controls) undergoing skull base surgery as an adjunct to suture for sealing the duramater, in which the efficacy outcome was measured post-operatively as verified cerebrospinal fluid(CSF) leaks or pseudomeningocoele, or treatment failure during surgery. In this study, superiority overcurrent practice (which included suture, duraplasty and fibrin and polymer sealants or combinations ofthese) could not be documented. The numbers of subjects experiencing an efficacy outcome eventwere 25 (6.9%) and 30 (8.2%) for TachoSil and current practice treated patients, respectively,providing an Odds Ratio of 0.82 (95% CI: 0.47, 1.43). However, the 95% confidence intervals for theodds ratio results indicated that TachoSil had similar efficacy to current practice. In this study twoapplication techniques for TachoSil were evaluated: application of TachoSil over the dura andapplication of TachoSil on both sides of the dura. The results did not support the second method.

TachoSil was found to be well tolerated and safe for use as an adjunct to dura mater closure inneurosurgery.

Limited data are available to support efficacy and safety of TachoSil in the paediatric population. Inclinical studies, a total of 36 paediatric patients aged 0-13 years were treated with TachoSil in hepaticsurgery. One study was prematurely stopped after enrolment of 16 of 40 planned patients. In a furtherstudy, 8 paediatric subjects were enrolled in a comparative design, additional 12 subjects wereenrolled open-label.

No valid data on immunogenicity is available.

TachoSil is intended for epilesional use only. Intravascular administration is contraindicated.

Therefore, intravascular pharmacokinetic studies were not performed in man.

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

In animal studies, TachoSil biodegrades after administration to a wound surface with few remnantsleft after 13 weeks. Complete degradation of TachoSil was seen in some animals 12 months after itsadministration to a liver wound, whereas small remnants were still observed in others. The degradationwas associated with infiltration of granulocytes and formation of resorptive granulation tissueencapsulating the degraded remnants of TachoSil. No evidence of local intolerability has beenobserved in animal studies.

From the experience in humans there have been isolated cases where remnants were observed ascoincidental findings with no signs of functional impairment.

Single dose toxicity studies in different species of animals have shown no signs of acute toxic effects.

6 PHARMACEUTICAL PARTICULARS

Equine collagen

Human albumin

Riboflavine (E101)

Sodium chloride

Sodium citrate (E331)

L-arginine-hydrochloride.

Not applicable.

3 years.

Once the foil sachet is opened, TachoSil must be used immediately.

Do not store above 25 ºC.

Each sealant matrix is packed in a PET-GAG blister sealed with a coated PE foil. The blister is packedin an aluminium-bonded foil sachet with a desiccant bag included and packed in a folding carton.

Package with 1 matrix of 9.5 cm x 4.8 cm

Package with 2 matrices of 4.8 cm x 4.8 cm

Package with 1 matrix of 3.0 cm x 2.5 cm

Package with 5 matrices of 3.0 cm x 2.5 cm

Package with 1 pre-rolled matrix of 4.8 cm x 4.8 cm

Not all pack sizes may be marketed.

TachoSil comes ready to use in sterile packages and must be handled accordingly. Use onlyundamaged packages. Once the package is opened, post-sterilisation is not possible. The outeraluminium foil sachet may be opened in a non-sterile operating area. The inner sterile blister must beopened in a sterile operating room area. TachoSil should be used immediately after opening the innersterile cover.

TachoSil is used under sterile conditions. Prior to application the wound area should be cleansed, e.g.,from blood, disinfectants, and other fluids. After removal of the conventional, flat TachoSil from thesterile package it should be pre-moistened in saline solution and then applied immediately. Theyellow, active side of the matrix is applied to the bleeding/leaking surface and held against it with agentle pressure for 3-5 minutes. This procedure enables an easy adhesion of TachoSil to the woundsurface.

After removal of the pre-rolled TachoSil from the sterile package it should be applied immediatelythrough the trocar without pre-moistening. While unrolling the matrix the yellow, active side of thematrix is applied to the bleeding/leaking surface using e.g., a pair of cleansed forceps and held againstit with a moist pad under gentle pressure for 3-5 minutes. This procedure enables an easy adhesion of

TachoSil to the wound surface.

Pressure is applied with moistened gloves or a moist pad. Due to the strong affinity of collagen toblood, TachoSil may also stick to surgical instruments, gloves or adjacent tissues covered with blood.

This can be avoided by cleansing surgical instruments, and gloves and adjacent tissues beforeapplication. It is important to note that failure to adequately clean adjacent tissues may causeadhesions (see section 4.4). After pressing TachoSil to the wound, the glove or the pad must beremoved carefully. To avoid TachoSil from being pulled loose it may be held in place at one end, e.g.,with a pair of forceps.

Alternatively, e.g., in case of stronger bleeding, TachoSil may be applied without pre-moistening,while also pressing gently to the wound for 3-5 minutes.

The active side of TachoSil should be applied so that it extends 1-2 cm beyond the margins of thewound. If more than one matrix is used, they should overlap. TachoSil can be cut to the correct sizeand shaped if too large.

In neurosurgery, TachoSil should be applied on top of the primary dura closure.

Pre-rolled TachoSil can be used for both open surgery and in minimally invasive surgery, and it canpass through a 10 mm or larger port or trocar.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Corza Medical GmbH

Speditionstraße 2140221 Düsseldorf

Germany

EU/1/04/277/001-005

Date of first authorisation: 8 June 2004

Date of latest renewal: 30 April 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu/.