ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
EVICEL solutions for sealant
2.
The active ingredients are as follows:
1 ml vial
2 ml vial
5 ml vial
Component 1
Human clottable protein
containing mainly fibrinogen and
fibronectin *
50 – 90 mg
100 – 180 mg
250 – 450 mg
Component 2
Human thrombin
800 – 1,200 IU
1,600 – 2,400 IU
4,000 – 6,000 IU
* Total quantity of protein is 80 - 120 mg/ml
For a full list of excipients see section 6.1.
3.
Solutions for sealant.
Clear or slightly opalescent solutions.
4.
EVICEL is used as supportive treatment in surgery where standard surgical techniques are
insufficient, for improvement of haemostasis (see section 5.1).
EVICEL is also indicated as suture support for haemostasis in vascular surgery.
The use of EVICEL is restricted to experienced surgeons.
Posology
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 clinical trials in
vascular surgery, the individual dosage used was up to 4 ml, whereas in retroperitoneal or intra-
abdominal surgery the individual dosage used was up to 10 ml. However, 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.
2
Method and route of administration
For epilesional use.
Prepare the solution as described in section 6.6.
Before application, the surface of the wound should be as dry as possible. See section 6.6 for more
detailed instructions.
EVICEL must not be applied intravascularly.
Hypersensitivity to the active substances or to any of the excipients.
For epilesional use only. Do not apply intravascularly.
Life threatening thromboembolic complications may occur if the product is unintentionally applied
intravascularly.
EVICEL should be applied as a thin layer. Excessive clot thickness may negatively interfere with the
product’s efficacy and the wound healing process.
Air or gas embolism has occurred with the use of spray devices employing pressure regulator 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.
When applying EVICEL using a spray device, the pressure should be within the range recommended
by the spray device manufacturer. In the absence of a specific recommendation the pressure should
not exceed 1.4-1.7 bars. EVICEL should not be sprayed at a distance closer than the recommended
by the spray device manufacturer. In the absence of a specific recommendation EVICEL should not
be sprayed closer than 10-15 cm from the tissue surface. When spraying EVICEL, changes in blood
pressure, pulse, oxygen saturation and end tidal CO
2
should be monitored because of the possibility of
occurrence of air or gas embolism.
When using accessory tips with this product, the instructions for use of the tips should be followed.
Adequate data are not available to support the use of this product in tissue gluing, neurosurgery,
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.
As with any protein product, allergic type hypersensitivity reactions are possible. 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.
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 infections agents cannot be totally excluded.
This also applies to unknown or emerging viruses and other pathogens.
3
The measures taken are considered effective for enveloped viruses such as HIV, Hepatitis C Virus and
Hepatitis B Virus and for the non-enveloped virus Hepatitis A Virus. 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
erythropoyesis (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.
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.
The safety of fibrin sealants/haemostatics for use in human pregnancy or during breast-feeding 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 post-natal development.
Therefore, the product should be administered to pregnant and lactating women only if clearly
needed.
Not relevant.
Adverse reactions which may be reported in association with fibrin sealants are described below.
Since no such reactions have been reported during clinical trials with EVICEL, the frequency of these
events with EVICEL is not known.
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 anti-histamines. 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 event and DIC, and there is also a
risk of anaphylactic reaction (see 4.4).
For safety with respect to transmissible agents, see 4.4.
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 events listed
below was common (defined as > 1/100, < 1/10).
4
MedDRA System Organ Class
Preferred Term
Adverse Reactions in Retroperitoneal or Intra-Abdominal Surgery Study
Infections and infestations
Abdominal abscess
Adverse Reactions in Vascular Surgery Study
Infections and infestations
Graft infection, Staphylococcal infection
Vascular disorders
Haematoma
General disorders and administration site
conditions
Oedema peripheral
Investigations
Decreased haemoglobin
Injury, Poisoning and Procedural
Complications
Incision site haemorrhage
Vascular graft occlusion
Wound
Post procedural haematoma
Post-operative wound complication
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.
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.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: local haemostatics, ATC code: B02BC
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 form
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.
Clinical studies demonstrating haemostasis and suture support were conducted in a total of 147
patients (75 with EVICEL, 72 with control) undergoing vascular surgery with PTFE grafts and in a
5
total of 135 patients (66 with EVICEL, 69 with control) undergoing retroperitoneal and intra-
abdominal surgery.
Data are 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 2 years.
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
125
I-thrombin it was
shown that a slow absorption of biologically inactive peptides resulting from the breakdown of
thrombin occurred, reaching a C
max
in the plasma after 6-8 hours. At the C
max
, 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
Studies performed in bacteria to determine mutagenicity were negative for Thrombin alone,
Biological Active Component (containing fibrinogen, citrate, glycine, tranexamic acid, and arginine
hydrochloride), TnBP alone, and Triton X-100 alone at all concentrations tested. All concentrations of
the combination of TnBP and Triton X-100 also tested negative in assays performed to determine
mammalian cell mutageneicity, chromosomal aberrations and micronuclei induction.
After local application, absorption of thrombin into the plasma is slow and consists principally of
thrombin degradation products which are eliminated.
No toxicological effects due to the solvent detergent reagents (TnBP and Triton X-100) used in the
virus inactivation procedure are expected since the residual levels are less than 5 µg/ml.
Neurotoxicity studies performed with EVICEL confirmed that subdural administration in the rabbit
was not associated with any evidence of neurotoxicity. Neurobehavioral observations for 14±1 days
showed no abnormal findings. No major macroscopic signs of local intolerance and no treatment –
related macroscopic findings were observed. Analysis of cerebrospinal fluid did not reveal major
signs of inflammation.
6.
6.1 List of excipients
Human fibrinogen vial
:
Arginine hydrochloride
Glycine
Sodium chloride
Sodium citrate
Calcium chloride
Water for injections
Human thrombin vial
:
Calcium chloride
Human albumin
Mannitol
Sodium acetate
6
Water for injections
Each ml contains 11.6-12.9 mg sodium.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
The approved shelf life of EVICEL is 16 months storage at ≤ -18
o
C.
After thawing, unopened vials can be stored at 2 - 8C and protected from light, for up to 25 days. The
Fibrinogen and Thrombin components are stable at room temperature for up to 24 hours.
6.4 Special precautions for storage
Store in a freezer at or below -18C. Keep the vials in the outer carton in order to protect from light.
Do not refreeze.
After thawing, unopened vials can be stored at 2-8C and protected from light, for up to 25 days,
without being frozen again during this period. The new expiry date at 2-8C 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 room temperature for up to 24 hours but once
drawn up into the application device, they 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), 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.
Not all pack sizes may be marketed.
6.6 Instructions for use, handling and disposal
The instructions for use are also described in the healthcare professionals package leaflet part.
Thawing
:
The vials should be thawed in one of the following ways:
2-8°C
(refrigerator): vials thaw within 1 day, or
20-25°C
(room temperature): vials thaw within 1 hour, or
37ºC
(e.g. water bath, using aseptic technique, or by warming vials in the hand): vials should be
thawed within 10 minutes and must not be left at this temperature for longer than 10 minutes or until
fully thawed. The temperature must not exceed 37ºC.
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.
7
EVICEL should 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 are provided with the package of the application device
and of the accessory. 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.
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
EVICEL can be sprayed using
pressurized CO
2
or compressed air.
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 μm 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, the pressure should be within the range recommended
by the spray device manufacturer. EVICEL should not be sprayed at a distance closer than the
recommended by the spray device manufacturer. When spraying EVICEL, changes in blood pressure,
pulse, oxygen saturation and end tidal CO
2
should be monitored because of the possibility of
occurrence of air or gas embolism.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Omrix Biopharmaceuticals S.A.
200 Chaussée de Waterloo
B-1640 Rhode-St-Genèse
Belgium
Tel: +32 2 359 91 23
Fax: +32 2 359 9127
8.
EU/1/08/473/001
EU/1/08/473/002
EU/1/08/473/003
9.
06/10/08
8
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
9
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
10
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Omrix Biopharmaceuticals Ltd.
MDA Blood Bank
Sheba Hospital
Ramat Gan 52621
POB 888
Kiryat Ono 55000
Israel
Name and address of the manufacturer responsible for batch release
Omrix Biopharmaceuticals S.A.
200 Chaussée de Waterloo
1640 Rhode-St-Genèse
Belgium
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 11-01-05
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning
before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version RMP-002-01 of the Risk Management Plan (RMP)
presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of
the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
11
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the EMEA
Official batch release: in accordance with Article 114 Directive 2001/83/EC as amended, the official
batch release will be undertaken by a state laboratory or a laboratory designated for that purpose.
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton box containing 2 vials
1.
EVICEL solutions for sealant
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Solutions for sealant
The active substances are as follows:
Component 1: 1 vial containing 1 ml of human clottable protein (50 – 90 mg/ml)
Component 2: 1 vial containing 1 ml of human thrombin (800 – 1200 IU/ml).
The active substances are as follows:
Component 1: 1 vial containing 2 ml of human clottable protein (50 – 90 mg/ml)
Component 2: 1 vial containing 2 ml of human thrombin (800 – 1200 IU/ml).
The active substances are as follows:
Component 1: 1 vial containing 5 ml of human clottable protein (50 – 90 mg/ml)
Component 2: 1 vial containing 5 ml of human thrombin (800 – 1200 IU/ml).
3.
LIST OF EXCIPIENTS
Human Fibrinogen: arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride,
water for injections.
Human Thrombin: calcium chloride, human albumin, mannitol, sodium acetate, water for injections.
4.
Solutions for sealant
The active substances are as follows:
Component 1: 1 vial containing 1 ml of human clottable protein (50 – 90 mg/ml)
Component 2: 1 vial containing 1 ml of human thrombin (800 – 1200 IU/ml).
The active substances are as follows:
Component 1: 1 vial containing 2 ml human clottable protein (50 – 90 mg/ml)
Component 2: 1 vial containing 2 ml of human thrombin (800 – 1200 IU/ml).
The active substances are as follows:
Component 1: 1 vial containing 5 ml of human clottable protein (50 – 90 mg/ml)
Component 2: 1 vial containing 5 ml of human thrombin (800 – 1200 IU/ml).
15
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For epilesional use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Do not apply intravascularly
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not re-freeze once thawed.
Store in the outer carton at -18°C or colder , to protect from light. After thawing, store unopened vials in the
outer carton at 2-8°C for up to 25 days starting on:
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product should be discarded in accordance with local requirements.
Omrix Biopharmaceuticals S.A.
200 Chaussée de Waterloo
B-1640 Rhode-St-Genèse
EU/1/08/473/001
EU/1/08/473/002
EU/1/08/473/003
13. BATCH NUMBER
Lot
16
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label
1.
Human fibrinogen:
EVICEL solutions for sealant
Component 1: Human clottable protein 50 – 90 mg/ml
2.
METHOD OF ADMINISTRATION
For epilesional use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml
2 ml
5 ml
6.
OTHER
To be used as two-components product with supplied device.
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label
1.
Human thrombin:
EVICEL solutions for sealant
Component 2: Human thrombin 800-1200 IU/ml
2.
METHOD OF ADMINISTRATION
For epilesional use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml
2 ml
5 ml
6.
OTHER
To be used as two-components product with supplied device.
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
EVICEL solutions for sealant
Human fibrinogen, human thrombin
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell you doctor or pharmacist.
In this leaflet
:
1.
What EVICEL is and what it is used for
2.
Before you are treated with EVICEL
3.
How to use EVICEL
4.
How to store EVICEL
6.
Further information
1.
WHAT EVICEL
IS AND WHAT IT IS USED FOR
EVICEL is a Human Fibrin Sealant which is supplied as a package containing two separate vials, each
containing 1 ml, 2 ml or 5 ml of solution (Fibrinogen and Thrombin respectively) Human Fibrinogen and
Human Thrombin.
An application device and appropriate accessory tips are supplied separately.
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.
EVICEL is applied during surgical operations, to reduce bleeding and oozing during and after the operation.
It is dripped or sprayed onto cut tissue where it forms a thin layer that seals the tissue and stops bleeding.
EVICEL can also be used in blood vessels surgery and in surgery taking place in the area between the
bowels and the posterior abdominal wall.
2.
BEFORE YOU ARE TREATED WITH EVICEL
Do not use EVICEL
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.
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:
gluing tissues together
surgery to the brain or spinal cord
21
5
Possible side effects
controlling bleeding in the stomach or intestines by applying the product through an endoscope
(tube)
sealing surgical repairs to the intestines.
Apply EVICEL as a thin layer. Excessive clot thickness may negatively interfere with the product’s
efficacy and the wound healing process.
Air or gas embolism has occurred with the use of spray devices employing pressure regulator 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.
When applying EVICEL using a spray device, be sure to use the pressure within the range
recommended by the spray device manufacturer. In the absence of a specific recommendation avoid
using pressure above 1.4-1.7 bars. Do not spray at a distance closer than the recommended by the
spray device manufacturer. In the absence of a specific recommendation avoid spraying closer than 10-
15 cm from the tissue surface. When spraying EVICEL, changes in blood pressure, pulse, oxygen
saturation and end tidal CO
2
should be monitored because of the possibility of occurrence of air or gas
embolism.
When using accessory tips with this product, be sure to follow carefully the instructions for use.
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 of the medicinal product in order to
trace any possible infection source.
Using other medicines
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even
those not prescribed.
Pregnancy and 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.
Pediatric use
Data are too limited to support the safety and effectiveness of EVICEL in children.
22
3.
HOW TO USE EVICEL
The doctor treating you will administer EVICEL during surgery.
During your operation, your doctor will drip or spray EVICEL onto raw tissue during operations, 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.
23
4.
POSSIBLE 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 (1 to 10 patients in 10,000), 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 (nettle-rash), 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 a causal relation to the
application of EVICEL could not be excluded. After abdominal surgery some patients presented with an
abscess, and in vascular surgery some cases of an occluded graft occurred which had do be re-operated.
5.
HOW TO STORE EVICEL
Keep out of the reach and sight of children.
Store in a freezer at -18°C or colder.
Do not use EVICEL after the expiry date which is stated on the label as well as 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. Do not refreeze. After thawing, unopened
vials can be stored at 2-8°C and protected from light, for up to 25 days.
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.
6.
FURTHER INFORMATION
What EVICEL contains
The active ingredients are as follows:
Component 1: Human clottable protein (50 - 90 mg/ml)
Component 2: Human thrombin (800 - 1,200 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.
Pack sizes
EVICEL is available in the following sizes: 2 x 1 ml, 2 x 2 ml and 2 x 5 ml.
All packs sizes may not be marketed in all countries.
24
What EVICEL looks like and contents of the pack
EVICEL is a Human Fibrin Sealant which is supplied 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 (1ml, 2ml or
5ml) 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.
Marketing Authorisation Holder:
Omrix Biopharmaceuticals S.A.
200 Chaussée de Waterloo
B-1640 Rhode-St-Genèse
Belgium
Tel: +32 2 359 91 23
Fax: +32 2 359 91 27
For any information about this medicine, please contact the Manufacturer:
Pharmacovigilance Department
Omrix Biopharmaceuticals Ltd
Plasma Fractionation Institute
Sheba Hospital, Tel Hashomer
Ramat Gan 52621, Israel
Tel: +972-3-5316512
Fax: +972-3-5316590
This leaflet was last approved in {MM/YYYY}
The following information is intended for medical or healthcare professionals only.
INSTRUCTIONS FOR USE
Read this before you open the package
EVICEL comes in sterile packages and therefore it is important to use
only
undamaged packages which have
not been opened (post-sterilisation is not possible).
Preparation
No needles are involved in the preparation of EVICEL for administration. Draw the contents of the two vials
into the administration device following the instructions for use in the device package.. Both syringes
should be filled with equal volumes, and should not contain air bubbles. Any unused product or waste
material should be disposed of in accordance with local requirements. The solutions should be clear or
slightly opalescent. Do not use solutions that are cloudy or have deposits.
STORAGE OF EVICEL
Do not use after the expiry date stated on the carton and label.
Keep out of reach and sight of children.
Fibrinogen and Thrombin:
25
Long term storage
Store in a freezer at -18°C or colder. Do not use after the expiry date stated on the carton.
Short term storage
Store at 2C-8C (in a refrigerator) for no more than 25 days. The date on which refrigerator storage was
started should be marked on the carton in the space provided. Do not re-freeze.
Fibrinogen and Thrombin are stable at room temperature for 24 hours but when they have been drawn up
into the administration device, they must be used immediately.
Application Device
:
Store separately from the Fibrinogen and Thrombin, at room temperature.
Thawing
The vials should be thawed in one of the following ways:
2-8°C
(refrigerator): vials thaw within 1 day, or
20-25°C
(room temperature): vials thaw within 1 hour, or
37ºC
(e.g. water bath, using aseptic technique, or by warming vials in the hand): vials should be thawed
within 10 minutes and must not be left at this temperature for longer than 10 minutes or until fully thawed.
The temperature must not exceed 37ºC.
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 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 are provided with the package of the application device and of the
accessory.
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.
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
EVICEL can be sprayed using
pressurised CO
2
or compressed air.
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 μm 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 to be used 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 range
recommended by the spray device manufacturer. Do not spray at a distance closer than the recommended by
26
the spray device manufacturer. When spraying EVICEL, changes in blood pressure, pulse, oxygen
saturation and end tidal CO
2
should be monitored because of the possibility of occurrence of air or gas
embolism.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
27
Source: European Medicines Agency
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