ישראל - עברית - Ministry of Health
עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי
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Human Surgical Sealant
1.Nameof the MedicinalProduct
EVICEL ® Human SurgicalSealant
2.Qualitative and QuantitativeComposition
The active ingredients areas follows:
1 ml of solution 2 ml of solution 5 ml of solution
Human clottable protein containing
mainly fibrinogen and fibronectin*
50 – 90 mg
100 – 180 mg
250 – 450 mg
800 – 1,200 IU
1,600 – 2,400IU
4,000 – 6,000IU
Calcium Chloride 5.6 – 6.2 mg 11.2 – 12.4 mg 28 – 31 mg
* Total quantity of protein is 80 - 120 mg/ml.
For excipients see section6.1.
Solutions for sealant.
General haemostasis : EVICEL ®
is used assupportive treatment in surgery wherestandardsurgical
techniques are insufficient, for improvement of haemostasis.
Efficacy has been demonstrated in liversurgery and orthopaedic surgery (see 5.1).
4.2. Posologyand Method ofAdministration
The use of EVICEL ®
is restricted to experienced surgeons
The volumeof EVICEL ®
to be applied and the frequency ofapplicationshouldalways be oriented
towards the underlying clinical needs of the patient.
Thedose tobeappliedis governedby variablesincluding,but not limitedto, the typeofsurgical
intervention, the size of thearea and themode ofintended application and the numberof applications.
Application ofthe productmust beindividualisedby the treating physician. Inclinical trials,dosages have
typically ranged from5 to10 mlof thecombinedproduct. Forsomeprocedures(e.g. liver traumata, or the
sealing of large burnedsurfaces) larger volumes may be required.
The initial volume of the product to be applied at a chosen anatomicsite or targetsurface area should be
sufficient to entirely cover the intended application area. The application can be repeated, if necessary.
EVICEL ® should be dripped or sprayedonto the tissue in short bursts(0.1 −0.2 ml) to produce a thin,
The maximum recommendeddosage ofcombinedproduct is 20mlforadults,10 ml forchildren and5 ml
In orthopaedic surgery, there are insufficientdata available to recommend the use of EVICEL ®
of less than18years of age.
4.2.2.Method andRoute ofAdministration
For epilesional use.
Prepare the solutions as described in Section 6.6. Before application, the surface of the wound shouldbe
as dry aspossible. See 6.6for more detailed instructions.
must not be applied intravascularly.
Hypersensitivity tothe active substancesor any of the excipients.
4.4. Special Warnings and Precautions for Use
For epilesional use only. Do not apply intravascularly.
Adequate data are not available to support the use ofthis product in tissue glueing, application
through an endoscope fortreatment of bleeding or ingastrointestinal anastomoses.
Life threatening thromboembolic complications mayoccur if the product isunintentionally applied
Air or gas embolismhasoccurredwith the use of spray devicesemploying pressureregulators to
administer EVICEL ®
. This event appears toberelated to the useof thespraydevice athigher
than recommended pressures and in close proximityto the surfaceof the tissue.When applying
usinga spray device,besureto use thepressurewithinthe pressurerange
recommended by thespray device manufacturer.In the absenceof a specificrecommendation
avoid usingpressureabove 1.4-1.7 bars. Do notspray closerthan thedistance recommended by
the spray device manufacturer. Intheabsenceofa specific recommendation avoidspraying
closer than10-15cm fromthesurface ofthetissue. WhensprayingEVICEL ®
pressure, pulse, oxygensaturationandend tidalCO2should bemonitoredbecause of the
possibility of occurrence of air or gas embolism.
Beforeadministrationof EVICEL ®
, careis tobe taken that parts ofthe bodyoutside the desired
application area aresufficiently protected (covered)to prevent tissue adhesionat undesired sites.
As with any proteinproduct, allergictype hypersensitivity reactions are possible. Signs of
hypersensitivity reactions include hives, generalisedurticaria, tightness of the chest, wheezing,
hypotensionand anaphylaxis.Ifthese symptoms occur, theadministrationhas to bediscontinued
In case of shock, standardmedical treatment for shock should be implemented.
Standard measurestoprevent infectionsresulting from theuse ofmedicinal products prepared
from human blood orplasma include selection ofdonors, screening of individual donationsand
plasmapools for specificmarkersof infection and the inclusionof effective manufacturingsteps
for the inactivation/removal of viruses. Despite this, when medicinal productsprepared from
humanbloodor plasma are administered, the possibility of transmitting infectionsagents cannot
be totally excluded. Thisalso applies tounknown oremerging viruses and otherpathogens. The
measures taken areconsidered effective for enveloped viruses such as HIV, HCV and HBV.
The measurestaken may be of limitedvalue against non-enveloped virusessuch asHAV and
ParvovirusB19 infectionmay be serious forpregnant women (foetal infection)and for individuals
with immunodeficiency or increased erythropoeisis(e.g. haemolytic anaemia).
It is stronglyrecommended that every time that EVICEL ®
is administered toapatient, the name
and batch number of the product are recorded in order to maintaina link between the patient and
the batch of the product.
4.5.Interactionwith Other Medicaments and OtherForms of Interaction
No formal interaction studies have beenperformed. Similar to comparable products orthrombin solutions,
the product may be denaturedafter exposure tosolutionscontaining alcohol, iodineor heavy metals (e.g.
antiseptic solutions). Suchsubstancesshould be removed to the greatest possible extent before applying
The safety of fibrin sealants/haemostatics for useinhuman pregnancy or during breast-feeding has not
been established incontrolled clinical trials. Experimental animal studiesare insufficient to assess the
safetywith respectto reproduction, development ofthe embryoor foetus, thecourseof gestationand
peri-and post-natal development. Therefore, theproduct should be administered to pregnant and
lactatingwomen only if clearly needed.
4.7.Effects onAbilitytoDrive and Use Machines
Hypersensitive or allergicreactions (which may include angioedema, burning andstinging at the
applicationsite, bronchospasm,chills, flushing, generalisedurticaria, headache, hives,hypotension,
lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) may
occur inrarecases inpatients treatedwith fibrinsealants/haemostatics. Inisolatedcases, these reactions
have progressed to severe anaphylaxis. Such reactions may especially be seen if the preparation is
applied repeatedly, or administered to patients known tobe hypersensitive to constituents of the product.
Antibodiesagainst components of fibrinsealant/haemostatic products may occur rarely.
Inadvertent intravascular injectioncould lead tothromboembolic event and DIC,and thereis alsoa risk of
A post marketing fatality was reported inassociationwith the use of EVICEL ®
device. Thecase involvedan attempt tostopactive bleedingby applying EVICEL ®
using aspray device
attachedtoawallunit atahigher thanrecommendedpressureforthe spray device. Inaddition, thespray
headwas placed at a distance from the bleeding sitethat was closerthan therecommended distance
guidelines for the application of the sealant. The patient suffered a fatal air embolism.
For safety with respect to transmissible agents, see 4.4.
As with any plasmaderivative, anaphylactic reactions may occur inrare cases.No adverse events of this
type werereported during the conduct of the clinical trials.
Mild reactionscanbemanagedwith anti-histamines. Severe hypotensive reactionsrequire immediate
intervention usingcurrent principlesof shock therapy.
No case of overdose has been reported.
Pharmacotherapeutic group: local haemostatics, ATC code: B02BC
The fibrin adhesion systeminitiates the last phase of physiological blood coagulation.
Conversionof fibrinogeninto fibrinoccursby the splittingoffibrinogen into fibrinmonomers and
fibrinopeptides. The fibrinmonomersaggregate and form a fibrinclot.FactorXIIIa, which isactivated
form FactorXIII by thrombin, crosslinks fibrin. Calciumions are required for both the conversion of
fibrinogen and the crosslinkageof fibrin.
As wound healing progresses, increased fibrinolyticactivity is inducedby plasmin and decomposition of
fibrin to fibrindegradation products isinitiated.
Clinical studies demonstratinghaemostasisand sealing were conductedinliversurgery (liver resection
and livertransplantation)andorthopaedic surgery(total hip replacementand totalkneereplacement
surgery). In addition a Phase II study has been performed in vascularsurgery(carotid endarterectomy).
Study designsand patient numbers aresummarised inthe followingtable:
Surgical Procedure StudyDesign and Phase Number ofPatients
Liver resection Phase III; Single-blind,randomised, standard-
treatment active controlled,parallel-group, multicentre
study. Total 121;
Control group: 63
Living relateddonor liver
transplantation Phase II; Open label, active controlled, non-
randomised,comparative clinical study. Total 34;
Control group: 17
Liver resection and reduced
size liver transplantation Phase II; Open, non comparative, prospective study. 21 patients, all treated
Total Hip Replacement Phase III; Single-blind, randomised, controlled,
multicenterstudy. Total 97;
Control group: 43
Total Knee Replacement Phase III; Single-blind randomised controlled
multicentre study. Total: 59;
Control group: 30
Total Knee Replacement Phase III; Single blind, randomised, parallel group,
standard treatment control multicentre study. Total: 53;
Control group: 28
Total Hip Replacement Phase II; Open pilot study comparing three regimens
of administration of Quixil in THRwith matched
historical controls. 13 patients, all treated
Carotid Endarterectomy with
PTFE graft Phase II; Single blind, prospective, randomized, active
controlled pilot study. Total: 20
Control group: 10
* First generation of Human Surgical Sealant
The clinical trials in liver surgery included eight paediatric patients of which five were less than 2 years
old. In one study involving59 patientsundergoingtotal kneereplacement surgery, Quixil (first generation
of Human Surgical Sealant) was shown to be haemostaticallyeffective in patients treated with Low
Molecular Weight Heparinprior to surgery.
is intended for epilesionaluse only. Intravascular administrationis contraindicated. As a
consequence,intravascular pharmacokineticstudies were not performed in man.
Studies havebeen conductedinrabbitsto evaluatethe absorption andeliminationof thrombinwhen
applied to thecutsurface ofthe liverresulting frompartial hepatectomy. Using 125 I-thrombinit wasshown
that a slowabsorption of biologically inactive peptidesresulting fromthe breakdown of thrombin occurred,
in the plasma after 6-8hours. At the C
,the plasmaconcentration represented only 1-
2% of the applied dose.
Fibrinsealants/haemostaticsare metabolised in thesameway asendogenous fibrin, by fibrinolysisand
has beenclassified asnon-irritant in the Primary Cutaneous IrritationTest andslightly irritant in
the Ocular Irritation test. NeitherBAC nor thrombin solution inducesmutagenic effectsin the Amestest.
After local application, absorptionof thrombin into theplasma isslow and consists principallyof thrombin
degradation productswhichare eliminated.
No toxicological effectsdue to thesolvent detergentreagents(TnBP and TritonX-100) usedinthe virus
inactivation procedure areexpected since the residuallevels are less than 5 µg/ml.
Neurotoxicitystudies performedwith EVICEL ®
not associatedwith any evidence of neurotoxicity.
6.1. List of Excipients
Water for Injections
Thrombin Solution :
Water for Injections
This medicinal product must not be mixed with other medicinal products and should always be applied
with the device supplied.
6.4.Special Precautionsfor Storage
The vials must bestored inanuprightposition. Store at ≤-18°C.Keepthe vials in theoutercarton in
order to protect from light. Do not refreeze.
After thawing,unopened vials can bestored at 2 - 8 °C and protected from light, for up to 30 days.
WhenBAC2and Thrombin havebeen drawn upinto the administrationdevice theymust beused
6.5.Nature and Contents ofthe Container
consistsof apackage containing twoseparate vials(glass typeI) with rubber stoppers (type I),
eachcontaining 1ml, 2ml or 5mlofsolution(BAC2andThrombinrespectively), andan application
The CE-marked application device package containsa sterile,single-use, disposable two-syringe device
arranged in clear PVC tray,which is sealed with Tyvek peel paper. The sealed tray is contained in a
sealed pouchconstructedof paper/polyethylene and supplied in acardboard carton.
6.6Instructions forUse,Handling and Disposal
The vials should be thawedin one of the followingways:
2-8°C (refrigerator): vialsthaw within1 day, or
20-25°C (room temperature): vials thawwithin 1 hour,or
37ºC (e.g. water bath, using aseptic technique, or bywarming vials in the hand):vials thawwithin 10
minutes andmust not be left at this temperature for longer than 10minutes oruntil fully thawed. The
temperaturemust not exceed 37ºC.
Preparation (seeFigure 1)
The application device packagecontains aspeciallydesigneddevice for applying the product anda tube
with 0.2 μm bacteriological filter which is used tosupply pressurised gas tothe device toaerosolise
when applied byspraying. The application devicesare sterile aslong asthepackage is
unopenedand undamaged, and must only be usedonce.Noneedlesare involved in thepreparation of
Drawthe contents of the two vials into the administration device, followingthe instructionsinFigure 1.
Both syringes should be filled with equalvolumes, and should notcontain air bubbles.
Keeping the tip of the applicatorasclose to the tissuesurface aspossible, butwithout touching the tissue
during application, apply individualdrops tothearea tobe treated. Thedrops should beallowedto
separatefromeachother and from the tip of theapplicator. If the applicatortip becomes blocked, the
cathetertip can be cut back in 0.5 cm increments.
canbe sprayed usingpressurizedCO
Connect the short tube onthe application device to the male luer-lock endof the long gas tube. Connect
the femaleluer lockof the gas tube(with thebacteriostatic filter) toapressureregulatorcapable of
delivering 1to 2 bars pressure. Thepressureregulatorshould be used in accordance with the
manufacturer’s instructions. Utilizespray pressurethat is withinthe recommended guidelines by the
device manufacturer [e.g. a pressure of 1.4 to 1.7 bars(measured by gasflow)]..
Ensure thatdistance between the spray headand the application bed iswithin the recommended
guidelines bythe devicemanufacturer. The distance betweenthe nozzle andthe tissuesurfaceshould
ideallybe10to15cm.The product should then be sprayed onto the surface ofthe tissue in short bursts
(0.1 −0.2 ml) to form a thin, even layer. EVICEL ®
forms a clear filmover the area of application.
Any unusedproduct orwaste material should be disposed of in accordance withlocal requirements.
The solutionshould beclear orslightly opalescent. Donot usesolutions that are cloudy or have deposits.
Omrix Biopharmaceuticals Ltd. (+logo)
MDA Blood Bank, Sheba Hospital, Ramat Gan
POB 888, Kiryat Ono, 55000, ISRAEL
8.Date ofRevision of the Text
Figure 1. Instructionsfor Use oftheAdministration Device
Holding the syringe barrels with one hand, loosenthesyringe pistons by sliding them back andforth.
1. Insert the two vials (BAC2and
Thrombin) intothe two sterile vialcups.
The vial cupsmust be handled using
sterile technique. 2. Holding the vialcup, press thetopof
the vial intothe vial connectorwhich is
attached tothe applicator(asshown).
Repeat with the second vial.
3.Holding the syringbarrels with one
hand, aspirate both syringes slowly
(vials facingup). If needed, injectback
into vial and aspirate again to expel air. 4. While holding the syringe barrelswith
onehand, gently turn thevial connector
anti-clockwise withtheother hand. The
vial connector/vial/vial cupcombination
5 If sprayingis required, connect the tubing tothepressure regulator. The applicator is now
ready for use.