Consumer medicine information

Evicel

Fibrinogen; Thrombin

BRAND INFORMATION

Brand name

Evicel

Active ingredient

Fibrinogen; Thrombin

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Evicel.

What is in this leaflet?

This leaflet answers some common questions about EVICEL® Solutions for Fibrin Sealant. It does not contain all of the available information. All medicines have risks and benefits. Your doctor has weighed the risks against the benefits for you by using EVICEL® Solutions for Fibrin Sealant.

It does not take the place of talking to your doctor or pharmacist. If you have any concerns about having this medicine, ask your doctor or pharmacist.

Read this leaflet carefully before you start using this medicine

Keep this leaflet. You may need to read it again.

What is EVICEL® and what is it used for?

EVICEL® is a Fibrin Sealant which is supplied in Australia as a package containing two separate vials, each containing 1 mL, 2 mL or 5 mL of solution Human Fibrinogen and Human Thrombin, respectively.

An application device and appropriate accessory tips are supplied separately.

EVICEL® is applied during surgical operations to reduce bleeding and oozing during and after the operation. EVICEL® is also used to seal tissues during neurosurgery. It is dripped or sprayed onto cut tissue where it forms a thin layer that seals the tissue and/or stops bleeding.

EVICEL® can also be used in blood vessel surgery, in surgery taking place in the area between the bowels and the posterior abdominal wall, and in brain surgery.

How does EVICEL® work?

Fibrinogen is a concentrate of clottable protein and thrombin is an enzyme that causes clottable protein to coalesce. Thus, when the two components are mixed together they clot instantly.

Before you are given the EVICEL®

EVICEL® should not be given to you if

  • You are hypersensitive (allergic) to products made from human blood or to any of the other ingredients of EVICEL®.
    Signs of such reactions include hives, rash, tightness of the chest, wheezing, drop in blood pressure and breathing difficulties. If these symptoms occur, the administration has to be discontinued immediately.
  • The expiry date printed on the pack has passed.

Take special care with EVICEL®

  • When EVICEL® is applied during surgery, the surgeon must ensure that it is only applied onto the surface of tissue. EVICEL® must not be injected into tissue or blood vessels because it would cause clots which could be fatal.
  • The use of EVICEL® has not been studied in the following procedures, and there is therefore no information to show that it would be effective in these procedures:
    - controlling bleeding in the stomach or intestines by applying the product through an endoscope (tube)
    - sealing the stomach or the bowel in order to avoid leakage of their contents after they have been sutured
    - and in spinal procedures.
  • Life threatening air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer EVICEL®. 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. To avoid the risk of potentially life threatening air embolism EVICEL® should be sprayed using pressurised CO2 gas only. When spraying EVICEL®, 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.
  • The use of EVICEL® in patients undergoing radiotherapy within 7 days after surgery has not been evaluated. It is not known whether radiation therapy could affect the efficacy of fibrin sealant when used for suture line sealing in dura mater closure.
  • Nearby areas should be protected to make sure that EVICEL® is only applied onto the surface which is to be treated.
  • As with any product containing proteins, allergic type hypersensitivity reactions are possible. Signs of such reactions include hives, rash, tightness of the chest, wheezing, drop in blood pressure and anaphylaxis. If these symptoms occur, the administration has to be discontinued immediately.
  • When medicines are made from human blood or plasma, certain measures are put into place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of viruses/infections. Manufacturers of these products also include steps in the processing of the blood and plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded.
    This also applies to any unknown or emerging viruses, or other types of infections. The measures taken in the manufacture of fibrinogen and thrombin are considered effective for lipid coated viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and the non-enveloped virus, hepatitis A. The measures taken may be of limited value against parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals whose immune system is depressed or who have some types of anaemia (e.g. sickle cell disease or haemolytic anaemia).
    The healthcare professionals will record the name and batch number(s) of EVICEL® used in order to trace any possible infection source.

You must tell your doctor if you

  • are taking or have recently taken any other medicines, even those not prescribed.
  • You must tell your doctor, if you are pregnant, planning to become pregnant or breast feeding.
    There is not enough information available to know whether any particular risks are associated with the use of EVICEL® during pregnancy or whilst breast-feeding. However, since EVICEL® is used during a surgical operation, if you are pregnant or breast-feeding you should discuss the overall risks of the operation with your doctor.

Use in Children

Data is too limited to support the safety and effectiveness of EVICEL® in children.

How EVICEL® is given

The doctor treating you will administer EVICEL® during surgery.

During your operation, your doctor will drip or spray EVICEL® onto raw tissue, using an application device. This device allows equal amounts of the two components of EVICEL® to be administered at the same time, and ensures that they mix evenly, which is important for the sealant to have its optimal effect.

The amount of EVICEL® that will be applied depends on the surface area of tissue to be treated during the operation. It will be dripped onto the tissue in short bursts or sprayed in very small amounts (0.1-0.2 mL), to produce a thin, even layer. If application of a single layer of EVICEL® does not completely stop the bleeding, a second layer may be applied.

Case of overdose

No case of overdose has been reported.

Side effects

Like all medicines, EVICEL® can have side effects, although not everybody gets them.

EVICEL® is a fibrin sealant. Fibrin sealants in general may, in rare cases (may affect up to 1 in 1,000 people), cause an allergic reaction. If you experience an allergic reaction you might have one or more of the following symptoms: skin rash, hives or wheals (nettlerash), tightness of the chest, chills, flushing, headache, low blood pressure, lethargy, nausea, restlessness, increased heart rate, tingling, vomiting, or wheezing. No allergic reactions have so far been reported in patients treated with EVICEL®.

There is also a theoretical possibility that you could develop antibodies to the proteins in EVICEL®, which could potentially interfere with blood clotting.

If you feel unwell tell your doctor immediately, even if your symptoms are different from those just described.

If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

In clinical studies with EVICEL® some undesired events occurred for which causal relation to the application of EVICEL® could not be excluded.

Most serious side effects

  • Watery fluid coming out of your wound or nose (CSF leakage/CSF rhinorrhea)
  • Headache, nausea, and vomiting (due to Subdural Hygroma, which is accumulation of CSF in the subdural space)
  • Fever, or prolonged constipation, flatulence (due to abdominal abscess)

The frequency of the effects listed above was common (may affect up to 1 in 10 people).

  • Numbness or pain in your extremities, change in skin colour (due to Graft Occlusion or Thrombosis)

The frequency of this effect was uncommon (may affect up to 1 in 100 people).

Other side effects

Other side effects which were reported to be common during clinical trials with EVICEL® (i.e., may affect up to 1 in 10 people) included meningitis, fever, difficulties with blood clotting and accumulation of CSF fluid in the brain cavities (hydrocephalus). The frequency of all of these effects was common.

Side effects which were uncommon during clinical trials with EVICEL® (i.e., may affect up to 1 in 100 people) included infection, blood accumulation (haematoma), swelling, decreased haemoglobin, and post-operative wound complications (including bleeding or infection).

Product Description

What is in EVICEL®?

The active ingredients are as follows:

  • Component 1: Fibrinogen - human (50 - 90 mg/mL clottable protein)
  • Component 2: Thrombin - human (800 - 1200 IU/mL)

Other ingredients are:

  • Component 1: arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride and water for injections.
  • Component 2: calcium chloride, human albumin, mannitol, sodium acetate and water for injections.

EVICEL® in Australia is available in the following sizes: 2 mL (2 x 1 mL vials), 4 mL (2 x 2 mL vials) and 10 mL (2 x 5 mL).

What EVICEL® looks like and contents of the pack

EVICEL® is a Human Fibrin Sealant which is supplied in Australia as a package containing two separate vials, each containing 1 mL, 2 mL or 5 mL solution of Human Fibrinogen and Human Thrombin, respectively.

An application device and appropriate accessory tips are supplied separately. Fibrinogen and Thrombin are packaged together as two vials each containing the same volume (1 mL, 2 mL or 5 mL in Australia) of frozen, sterile solution, which is colourless or yellowish when thawed. Fibrinogen is a concentrate of clottable protein and Thrombin is an enzyme that causes clottable protein to coalesce. Thus, when the two components are mixed together they clot instantly.

How to store EVICEL®

Keep out of the reach and sight of children.

The vials must be stored in an upright position. Store in freezer at or below - 18°C.

Do not use EVICEL® after the expiry date which is stated on the label as well as on the carton after EXP. The expiry date refers to the last day of that month.

Keep the vials in the outer carton in order to protect from light. After thawing, unopened vials can be stored at 2-8°C and protected from light, for up to 30 days. Do not refreeze.

The Fibrinogen and Thrombin components are stable at room temperature for up to 24 hours but once drawn up into the application device, they must be used immediately.

Where can you get more information?

You can get more information from your doctor or pharmacist.

Name and Address of Sponsor:

Johnson & Johnson Medical Pty Ltd.
1-5 Khartoum Rd, North Ryde
NSW 2113, AUSTRALIA

Manufacturer:

Omrix Biopharmaceuticals Ltd.
MDA Blood Bank, Sheba Hospital,
Ramat Gan, POB 888,
Kiryat Ono 5510801, ISRAEL

Poison schedule of the medicine

Exempt from scheduling

Date of approval

22 October 2012

This leaflet was last revised on

08 April 2021

Art n°: TBC
©Johnson & Johnson Limited yyyy

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Evicel

Active ingredient

Fibrinogen; Thrombin

Schedule

Unscheduled

 

1 Name of Medicine

Human thrombin, Human fibrinogen and Factor XIII.

2 Qualitative and Quantitative Composition

Fibrinogen solution.

1 mL contains fibrinogen 80 to 120 mg/mL total protein (clottable protein (human) 50-90 mg).

Thrombin solution.

1 mL contains 800 to 1,200 IU thrombin (human).

Note.

1 IU (international unit) thrombin (human) is defined as the activity contained in 0.0853 mg of the first international standard of human thrombin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solutions for fibrin sealant.
The fibrinogen and thrombin solutions appear as white to slightly yellowish opaque masses when frozen, and as clear to slightly opalescent and colourless to slightly yellowish solutions when thawed.

4 Clinical Particulars

4.1 Therapeutic Indications

Evicel is used as supportive treatment in surgery where standard surgical techniques are insufficient, for improvement of haemostasis.
Evicel is also indicated as suture support for haemostasis in large vessel vascular surgery.
Evicel is indicated for suture line sealing in dura mater closure.

4.2 Dose and Method of Administration

Dosage.

The volume of Evicel to be applied and the frequency of application should always be oriented towards the underlying clinical needs of 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.
Application of the product must be individualised by the treating physician. In controlled clinical trials in vascular surgery the individual dosage used was up to 4 mL. For dural sealing in neurosurgery, doses of up to 8 mL were used, whereas in retroperitoneal or intra-abdominal surgery the individual dosage used was up to 10 mL. For some procedures (e.g. liver traumata) larger volumes may be required.
The initial volume 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 an approximate guide, if a layer of 1 mm thickness is produced by applying Evicel, the surface areas that can be covered by each of the kit sizes are given in Table 1.

Method and route of administration.

Evicel is for epilesional use only. Before application, the surface area of the wound should be as dry as possible (e.g. intermittent application of compresses, swabs, use of suction devices).
To avoid the risk of potentially life-threatening air embolism Evicel should be sprayed using pressurised CO2 gas only. The spraying of Evicel is limited to surgeons who are informed regarding the use of Evicel in conjunction with a pressure regulator.
The product should only be reconstituted and administered according to the instructions and with the devices recommended for this product.

Thawing.

Option 1.

37°C (water bath): transfer the frozen vials into a water bath using aseptic technique. (See Table 2).
Approximate thawing and warming for Evicel when using a 37°C water bath is:

Option 2.

20-25°C (room temperature): transfer vials into room temperature conditions. (See Table 3).
The approximate thawing and warming for Evicel when placed in room temperature is:

Option 3.

2-8°C (refrigerator): transfer vials into a refrigerator. (See Table 4).
The approximate thawing time for Evicel when placed in a refrigerator is:
Before use, the product must reach 20-30°C.

Preparation.

The solutions are clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.
Evicel should only be applied using the CE-marked Evicel Application Device and optional use of a tip accessory to the device. Leaflets giving detailed instructions for use of Evicel in conjunction with the application device and optional accessory tips are provided with the package of the application device and of the accessory tips. The accessory tips should only be used by persons adequately trained in laparoscopic, laparoscopic-assisted, thoracoscopic or open surgical procedures.
Draw the contents of the two vials into the application device, following the instructions for use in the device package. Both syringes should be filled with equal volumes, and should not contain air bubbles. No needles are involved in the preparation of Evicel for administration.
Evicel is for single use in one patient only. Discard any residue.

Application by dripping.

Keeping the tip of the applicator as close to the tissue surface as possible, but without touching the tissue during application, apply individual drops to the area to be treated. If the applicator tip becomes blocked, the catheter tip can be cut back in 0.5 cm increments.

Spray application.

To avoid the risk of life-threatening air embolism, Evicel should only be sprayed using pressurised CO2.
Connect the short tube on the application device to the male luer-lock end of the long gas tube.
Connect the female luer lock of the gas tube (with the 0.2 micrometer bacteriostatic filter) to a pressure regulator. The pressure regulator should be used in accordance with the manufacturer's instructions.
Information about the distance and pressure is provided in the device and tip Assembly Guides.
The product should then be sprayed onto the surface of the tissue in short bursts (0.1-0.2 mL) to form a thin, even layer. Evicel forms a clear film over the area of application.
When applying Evicel using a spray device, be sure to use only the pressure within the recommended pressure range by the spray device manufacturer. Do not spray closer than the distance recommended by the spray device manufacturer. When spraying the Evicel, 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.
When applying Evicel using a spray device, be sure to use a pressure and a distance from the tissue within the ranges recommended by the manufacturer. (See Table 5).

4.3 Contraindications

Known hypersensitivity to the active substances or to any excipient of Evicel.
Injection of Evicel into tissues is contraindicated. Such use has been associated with inadvertent intravascular injection, with thromboembolic complications. Evicel should be applied with caution to minimise any risk of intravascular application, for example, in coronary bypass surgery. Evicel should only be applied topically.
Additionally, soft tissue injection of Evicel carries the risk of an anaphylactic reaction and/or local tissue damage.
Spray application of Evicel should not be used in endoscopic procedures.
Evicel must not be used for sealing the suture line in dura mater if there are gaps of greater than 2 mm after suturing.
Evicel must not be used as a glue for the fixation of dural patches.
Evicel must not be used as a sealant when the dura mater cannot be sutured.

4.4 Special Warnings and Precautions for Use

General.

Administration of Evicel may result in allergic reactions in some patients. For patients with known allergic diathesis or a history of hypersensitivity to protein products, a careful risk-benefit assessment should be carried out prior to administration.
Signs of hypersensitivity reactions include hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the administration should be immediately discontinued. In case of shock, standard medical treatment for shock should be implemented.
Air or gas embolism, tissue rupture, or gas entrapment with compression, which may be life threatening, have occurred with the use of spray devices employing a pressure regulator to administer fibrin sealants such as Evicel. These events appear to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface.
Evicel spray application should only be used if it is possible to accurately judge the spray distance, especially during laparoscopy. Spray distance from tissue and pressure should be within the ranges recommended by the manufacturer.
When spraying Evicel, 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.
Spray devices and accessory tips provide instructions for use with recommendations for pressure ranges and proximity to tissue surface, which should be carefully followed.
Adequate data are not available to support use of Evicel in application through a flexible endoscope for treatment of bleeding or in gastrointestinal anastomoses.
Before administration of Evicel, care is to be taken that parts of the body outside the desired application area are sufficiently protected (covered) to prevent tissue adhesion at undesired sites.
The safety and effectiveness of Evicel used alone or in combination with biocompatible carriers in neurosurgical procedures or other surgeries involving confined spaces have not been established.
Evicel is not indicated for the treatment of massive and brisk arterial or venous bleeding. When used in these situations, Evicel is likely to be washed away in the flow of blood before haemostasis can be attained.
Injection into the nasal mucosa must be avoided, as severe allergic/anaphylactoid reactions have been observed and thromboembolic complications may occur in the area of the ophthalmic artery.
The use of Evicel in patients undergoing radiotherapy within 7 days after surgery has not been evaluated. It is not known whether radiation therapy could affect the efficacy of fibrin sealant when used for suture line sealing in dura mater closure.
Complete haemostasis should be achieved before application of Evicel to seal the dural suture line.
The use of Evicel as a sealant in transphenoidal, otoneurosurgical procedures and spinal procedures has not been studied.

Viral and prion risk.

Evicel is made from human plasma. Products made from human plasma may contain infectious agents which can cause disease, such as viruses and theoretically Creutzfeldt-Jakob Disease (CJD) agents. 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 infectious 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, Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV), and for the non-enveloped Hepatitis A Virus (HAV). The measures taken may be of limited value against 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 anaemia).
It is strongly recommended that every time Evicel is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
All infections thought by a clinician possibly to have been transmitted by Evicel should be reported by the clinician or other healthcare provider to Johnson and Johnson Medical.
Patients should be instructed to consult their clinician if symptoms of B19 virus infection appear (fever, drowsiness, chills and runny nose, followed about two weeks later by a rash and joint pain).

Use in the elderly.

Clinical trials included 121 patients of 65 years of age or older (30 undergoing retroperitoneal or intra-abdominal surgery, 24 undergoing liver surgery, 47 undergoing vascular surgery and 20 undergoing neurosurgery). No overall differences in effectiveness were observed between the elderly and younger patients within the age groups studied in randomised clinical trials. Many of the adverse reactions reported in the randomised clinical trials were single events. No age-related safety signals were reported during the clinical trials.

Paediatric use.

Data is too limited to support the safety and effectiveness of Evicel in children.
Of 135 patients undergoing retroperitoneal and intra-abdominal surgery who were included in the controlled study of Evicel, 4 patients treated with Evicel were aged 16 years or younger. Of these, 2 were children aged 2 and 5 years and 2 were adolescents of 16 years. No data are currently available for ages younger than 11 months. See Section 4.8 Adverse Effects (Undesirable Effects).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies have been performed. Evicel 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. Oxycellulose-containing preparations may reduce the efficacy of Evicel and should not be used as carrier materials.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Evicel on fertility has not been evaluated.
(Category B2)
The safety of fibrin sealants/haemostatics for use in humans 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 fetus, and the course of gestation. Therefore, the product should be administered to pregnant women only if clearly needed.
 The safety of fibrin sealants/haemostatics for use during breast-feeding has not been established in controlled clinical trials. Experimental animal studies are insufficient to assess the safety with respect to peri- and post-natal development.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the application site, bronchospasm, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, 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 constituents of the product. Mild reactions can be managed with antihistamines. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.
Antibodies against components of fibrin sealant/haemostatic products may occur rarely.
Inadvertent intravascular injection could lead to thromboembolic events and disseminated intravascular coagulation (DIC), and there is also a risk of anaphylactic reaction.
Comparisons of adverse events for Evicel and the comparators used in the three controlled clinical trials are displayed in Tables 6, 7 and 8.
Air or gas embolism has occurred with the use of spray devices employing pressure regulators to administer Evicel. This event appears to be related to the use of the spray device at higher than recommended pressures and in close proximity to the tissue surface.
The following adverse events which occurred during clinical studies were evaluated as having a possible causal relationship to treatment with Evicel. The frequency of all of the adverse reactions in retroperitoneal or intra-abdominal surgery and in neurosurgery was common (defined as > 1/100, < 1/10). The frequency of all of the adverse reactions in vascular surgery was uncommon (defined as > 1/1000, < 1/100). See Table 9.

Description of selected adverse reactions.

Adverse reaction rates in retroperitoneal or intra-abdominal surgery study.

Among 135 patients undergoing retroperitoneal and intra-abdominal surgery (67 patients treated with Evicel and 68 controls), no adverse events were considered to be causally related to the study treatment according to the investigator assessments. However, 3 serious adverse events (SAE) (one abdominal abscess in the Evicel group and one abdominal and one pelvic abscess in the control group) were considered by the Sponsor to be possibly related to study treatment.
In a study of 40 patients with age range 11 months to 17 years (20 patients treated with Evicel and 20 controls), two adverse events (pyrexia and coagulopathy) were considered possibly related to Evicel by the investigator.

Adverse reactions - vascular surgery.

In a controlled study involving 147 patients undergoing vascular grafting procedures (75 treated with Evicel and 72 controls), a total of 16 subjects were reported to have had a graft thrombosis/occlusion adverse event during the study period. The events were evenly distributed across treatment arms, with 8 each in the Evicel and the control groups.
A non-interventional post-authorisation safety study was conducted which involved 300 patients undergoing vascular surgery during which Evicel was used. Safety monitoring focused on the specific adverse reactions of graft patency, thrombotic events, and bleeding events. No adverse reactions were reported during the study.

Adverse reactions - neurosurgery.

In a controlled study involving 139 patients undergoing elective neurosurgical procedures (89 treated with Evicel and 50 controls), a total of 7 subjects treated with Evicel experienced nine AEs that were considered to be possibly related to the study product. These included intracranial hypotension (CSF leakage), CSF rhinorrhea, meningitis, headache, hydrocephalus, subdural hygroma, and haematoma.
The incidence of CSF leakage and the incidence of Surgical Site Infections were monitored as safety endpoints in the study. At 30 days post-operatively the incidence of SSIs was similar between the two treatment groups. Post-operative CSF leakage occurred within 30 days from treatment in 4/89 (4.5%) subjects treated with Evicel (two cases of CSF leakage with impaired wound healing and two cases of rhinorrhoea) and in 1/50 (2.0%) subjects treated with additional sutures.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No case of overdose has been reported.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 crosslinking of fibrin.
As wound healing progresses, increased fibrinolytic activity is induced by plasmin and decomposition of fibrin to fibrin degradation products is initiated.

Clinical trials.

The objective of the clinical development plan was to demonstrate the haemostatic efficacy of Evicel in a range of surgical procedures representative of those encountered in normal clinical practice. Two Phase III prospective, randomised, controlled studies were performed in which the objective was to evaluate the haemostatic efficacy of Evicel by determining the proportion of patients achieving haemostasis within a pre-determined time period after application of the fibrin sealant (time to haemostasis, TTH) as compared to the control therapy.
The first study evaluated the effectiveness of Evicel in achieving haemostasis in soft tissue bleeding during retroperitoneal or intra-abdominal surgery as compared with a well-established haemostatic agent, oxidized, regenerated cellulose (ORC) haemostat.
The second study was conducted in patients undergoing vascular surgical procedures on an end-to-side femoral or upper extremity arterial anastomosis utilising uncoated or heparin-coated polytetrafluoroethylene (PTFE). Control patients were treated with manual compression (MC).
A third study was conducted to evaluate the effectiveness and safety of Evicel as a sealant. A randomised, controlled study was conducted to demonstrate efficacy and safety of Evicel when used as an adjunct to dural sutures in cranial surgery to provide intra-operative watertight closure. Control group subjects were treated with standard methods for dural closure which included additional dural sutures and an adjunctive product (excluding fibrin sealant) if required to assure durability of closure. The study was prospectively stratified based on surgical approach (Supra-tentorial or posterior fossa). See Table 10.

Evicel in soft tissue bleeding.

This was a Phase III, prospective, randomised controlled clinical study to evaluate the safety and efficacy of Evicel. Efficacy was evaluated by the assessment of whether Evicel was non-inferior to ORC in achieving haemostasis during surgical procedures involving soft tissue bleeding in retroperitoneal and intra-abdominal surgery.
The study population comprised patients undergoing non-emergent retroperitoneal or intra-abdominal surgery procedures, wherein a soft tissue target bleeding site (TBS) was identified for which an adjunctive epilesional haemostat was indicated. Patients were stratified for age (16 years or less, and over 16 years) in order to collect data on use in paediatric patients.
The primary endpoint was haemostatic success, defined as the absence of bleeding at the TBS at 10 minutes following randomisation to treatment.
135 patients were enrolled and randomised and included in the intent to treat (ITT) analysis (66 to Evicel, 69 to ORC). This included 11 paediatric patients aged 16 years or less.
Evicel (2 x 5 mL) or ORC was applied to the TBS immediately after opening the randomisation envelope. Re-application was allowed at the surgeon's discretion within the 10-minute observation period.
The results from the ITT analyses clearly showed Evicel to be non-inferior to the ORC, and furthermore the data indicated a significant advantage for Evicel over ORC within 10 minutes (p < 0.05). Kaplan-Meier analysis shows that this advantage was consistent over the 10-minute period, with possibly the best advantage seen at around 2 minutes. Overall the treatment difference (log-rank test) was highly significant (p < 0.001) in favour of Evicel.

Evicel in vascular surgery.

This was a phase III, multicentre, prospective, randomised, controlled, parallel group study carried out at centres in the UK and US. The study population comprised patients undergoing vascular procedures utilising uncoated or heparin-coated PTFE prosthetic graft material, with at least one end-to-side anastomosis to a femoral or upper extremity artery.
The primary objective of the study was to evaluate whether the fibrin sealant Evicel reduces time to haemostasis during vascular surgical procedures on an end-to-side femoral or upper extremity arterial anastomosis utilising uncoated or heparin-coated PTFE compared to manual compression (MC).
The primary endpoint was haemostatic efficacy, defined as the absence of bleeding at the study anastomotic site (SAS) 4 minutes following randomisation to treatment. The SAS was the final anastomosis to the femoral or upper extremity artery, with the exception of the femoral-femoral procedure when the SAS was the proximal anastomosis performed as the final anastomosis in the procedure.
For each patient, one kit of Evicel was pre-prepared for administration prior to randomisation. A total of 147 patients were randomised. For patients randomised to Evicel, the required amount of product was administered by dripping onto the SAS using the application device supplied.
The primary effectiveness variable was the absence of bleeding at the SAS at 4 minutes following randomisation. The results for the full analysis set (FAS) were statistically significant in favour of Evicel compared to MC (p < 0.001). This was confirmed by the per protocol (PP) set and a 'worst case' analysis. The results for upper extremity and femoral procedures were similar.
In addition, a non-interventional post-authorisation safety study was conducted which involved 300 patients undergoing vascular surgery during which Evicel was used.
Evidence of efficacy and safety of Evicel in vascular surgery is limited to procedures on large vessels.

Evicel in neurosurgery.

This was a Phase III, multicentre, prospective, randomised, controlled study carried out at centers in Belgium, Finland, France, Germany, the Netherlands, the UK, and Australia. The study population comprised patients undergoing elective craniotomy/craniectomy for pathological processes in the posterior fossa (such as benign or malignant tumours, vascular malformation, and Chiari 1 malformations) or in the supratentorial region and who were demonstrated to have persistent cerebrospinal fluid (CSF) leakage following primary attempt at suture closure of the dural incision.
The primary objective of the study was to evaluate the safety and efficacy of Evicel for use as an adjunctive sealant to dural sutures in elective cranial surgery, to provide intraoperative watertight closure.
The primary effectiveness variable was the proportion of successes (intraoperative watertight closure) in the treatment of intraoperative CSF leakage. Success was defined as no CSF leakage from dural repair intraoperatively, during Valsalva maneuver (20 to 25 cm H2O for 5 to 10 seconds).
Subjects were randomised in a 2:1 ratio to Evicel or control, respectively. Randomisation was stratified by surgical approach: posterior fossa or supratentorial. A total of 139 patients were randomised (89 to Evicel and 50 to control treatment).
For patients randomised to Evicel, the required amount of product was administered by spraying or dripping, depending on the surgeon's preference, onto the entire length of the suture line using the application device supplied. In most cases Evicel was applied by spraying. If necessary, a second layer of Evicel could be applied, allowing 1 to 2 minutes between applications to allow for polymerisation.
The primary analysis based on the first 135 randomised subjects for the primary efficacy endpoint with missing data considered as failures revealed a higher success rate (p < 0.001) for Evicel.
Intra-operative watertight closure (successes) in intent to treat (ITT) population was achieved in 92.1% of Evicel-treated subjects (82/89 subjects) versus 38.0% of sutured subjects (19/50 subjects); a treatment difference of 54.1% (p < 0.001 from both the Fisher's exact test and the Chi-squared test). Primary effectiveness analysis was further supported by sensitivity analysis imputing missing data as best case and worst case, analysis of the PP Set and logistic analysis. For the primary endpoint, the Cochran Mantel-Haenszel (CMH) adjusted odds ratio (OR) was 24.87 (95% CI: 8.53 to 72.50; p < 0.001) indicating the robustness of Evicel treatment. Furthermore, a statistically significant treatment effect in favour of Evicel was observed for both the supratentorial (treatment difference 49.1%) and posterior fossa strata (treatment difference 75.7%), at the primary endpoint (p < 0.001).
Thus, Evicel was shown to be superior to standard surgical methods in achieving watertight closure following primary suture repair of the dura mater. This was confirmed by the PP analysis and a sensitivity analysis.

5.2 Pharmacokinetic Properties

Evicel is intended for epilesional use only. Intravascular administration is contraindicated. As a consequence, intravascular pharmacokinetic studies were not performed in man.
Studies have been conducted in rabbits to evaluate the absorption and elimination of thrombin when applied to the cut surface of the liver resulting from partial hepatectomy. Using 125I-thrombin it was shown that a slow absorption of biologically inactive peptides resulting from the breakdown of thrombin occurred, reaching a Cmax in the plasma after 6-8 hours. At the Cmax, the plasma concentration represented only 1-2% of the applied dose.
Fibrin sealants/haemostatics are metabolised in the same way as endogenous fibrin, by fibrinolysis and phagocytosis.

5.3 Preclinical Safety Data

Genotoxicity.

Neither fibrinogen nor thrombin solution induces mutagenic effects in bacterial cells.

Carcinogenicity.

Animal studies have not been performed to evaluate the carcinogenic potential of Evicel.

6 Pharmaceutical Particulars

6.1 List of Excipients

Fibrinogen solution.

Arginine hydrochloride, Glycine, Sodium chloride, Sodium citrate, Calcium chloride, Water for injection (WFI).

Thrombin solution.

Calcium chloride, Human albumin, Mannitol, Sodium acetate, Water for injection (WFI).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Deep frozen Evicel has a shelf life of 2 years. The vials must be stored in an upright position. The expiry date is stated on the package.

6.4 Special Precautions for Storage

Store in a freezer at or below -18°C.
Keep the vials in the outer carton in order to protect from light.
Do not refreeze.
The two deep frozen solutions must be defrosted prior to use. After thawing and warming to 20°C-30°C, the two solutions are mixed using the application device, supplied separately (see Section 4.2 Dose and Method of Administration).
After thawing, unopened vials can be stored at 2°C-8°C and protected from light for up to 30 days, without being frozen again during this period. The new expiry date at 2°C-8°C should be noted on the carton. At the end of this period the product has to be used or discarded.
The fibrinogen and thrombin components are stable at or below 25°C for up to 24 hours. Once drawn up into the application device, the solutions must be used immediately.

6.5 Nature and Contents of Container

Evicel is supplied as a package containing two separate vials (glass type I) with rubber stoppers (type I).

Evicel solutions for fibrin sealant, 2 mL.

Composite pack containing fibrinogen solution 1 mL vial and thrombin solution 1 mL vial.

Evicel solutions for fibrin sealant, 4 mL.

Composite pack containing fibrinogen solution 2 mL vial and thrombin solution 2 mL vial.

Evicel solutions for fibrin sealant, 10 mL.

Composite pack containing fibrinogen solution 5 mL vial and thrombin solution 5 mL vial.
An application device and appropriate accessory tips are supplied separately.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Evicel Solutions for Fibrin Sealant kit is composed of 2 components, namely a preparation containing human fibrinogen (component 1), and a preparation containing human thrombin (component 2). Since these are complex compositions, chemical structure is not applicable.

7 Medicine Schedule (Poisons Standard)

Exempt from Scheduling.

Summary Table of Changes