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ישראל - עברית - Ministry of Health

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עלון מידע עלון מידע (PIL)

28-11-2020

מרכיב פעיל:
CALCIUM CHLORIDE; PROTEIN CLOTTABLE; THROMBIN
זמין מ:
OMRIX BIOPHARMACEUTICALS LTD, ISRAEL
קוד ATC:
B05BA10
טופס פרצבטיות:
תמיסה
הרכב:
THROMBIN 800 - 1200 IU / 1 ML; CALCIUM CHLORIDE 5.6 - 6.20 MG / 1 ML; PROTEIN CLOTTABLE 50 - 90 MG / 1 ML
מסלול נתינה (של תרופות):
חיצוני בניתוח
סוג מרשם:
מרשם נדרש
תוצרת:
OMRIX BOPHARMACEUTICALS LTD, ISRAEL
קבוצה תרפויטית:
COMBINATIONS
איזור תרפויטי:
COMBINATIONS
סממני תרפויטית:
General haemostasis : Evicel is used as supportive treatment in surgery where standard surgical techniques are insufficient, for improvement of haemostasis. Efficacy has been demonstrated in liver surgery and orthopaedic surgery.
מספר אישור:
118 61 29895 02
תאריך אישור:
2013-01-31

מסמכים בשפות אחרות

עלון מידע עלון מידע - אנגלית

17-08-2016

מאפייני מוצר מאפייני מוצר - אנגלית

17-08-2016

עלון מידע עלון מידע - ערבית

28-11-2020

עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי

The formatof this leaflet hasbeen determinedby theMinistryof Health and thecontent thereof has beenchecked

and approved.

Physician's Leaflet

EVICEL ®

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

Component 1(BAC2)

Human clottable protein containing

mainly fibrinogen and fibronectin*

50 – 90 mg

100 – 180 mg

250 – 450 mg

Component 2(Thrombin)

Human Thrombin

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.

3.Pharmaceutical Form

Solutions for sealant.

4.Clinical Particulars

4.1.Therapeutic Indications

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

4.2.1.Posology

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,

even layer.

The maximum recommendeddosage ofcombinedproduct is 20mlforadults,10 ml forchildren and5 ml

for infants.

In orthopaedic surgery, there are insufficientdata available to recommend the use of EVICEL ®

in patients

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.

4.3.Contra-indications

EVICEL ®

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

intravascularly.

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

EVICEL ®

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 ®

,changes inblood

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

immediately.

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

parvovirus B19.

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 product

4.6.Pregnancyand Lactation

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

Not relevant.

4.8.Undesirable Effects

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

anaphylacticreaction (see4.4).

A post marketing fatality was reported inassociationwith the use of EVICEL ®

whenappliedusing aspray

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.

4.9.Overdose

No case of overdose has been reported.

5.Pharmacological Properties

5.1.Pharmacodynamic Properties

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;

Quixil* group:58

Control group: 63

Living relateddonor liver

transplantation Phase II; Open label, active controlled, non-

randomised,comparative clinical study. Total 34;

Quixil* group:17

Control group: 17

Liver resection and reduced

size liver transplantation Phase II; Open, non comparative, prospective study. 21 patients, all treated

with Quixil*

Total Hip Replacement Phase III; Single-blind, randomised, controlled,

multicenterstudy. Total 97;

Quixil* group:54

Control group: 43

Total Knee Replacement Phase III; Single-blind randomised controlled

multicentre study. Total: 59;

Quixil* group:29

Control group: 30

Total Knee Replacement Phase III; Single blind, randomised, parallel group,

standard treatment control multicentre study. Total: 53;

Quixil* group:25

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

with Quixil*

Carotid Endarterectomy with

PTFE graft Phase II; Single blind, prospective, randomized, active

controlled pilot study. Total: 20

Quixil* group:10

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.

5.2.Pharmacokinetic Properties

EVICEL ®

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,

reachingaC

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

phagocytosis.

5.3.Pre-clinical SafetyData

EVICEL ®

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 ®

confirmedthatsubduraladministrationinthe rabbitwas

not associatedwith any evidence of neurotoxicity.

6.Pharmaceutical Particulars

6.1. List of Excipients

BAC2 :

ArginineHydrochloride

Glycine

Sodium Chloride

Sodium Citrate

Calcium Chloride

Water for Injections

Thrombin Solution :

Human Albumin

Mannitol

Sodium Acetate

Water for Injections

6.2.Incompatibilities

This medicinal product must not be mixed with other medicinal products and should always be applied

with the device supplied.

6.3.Shelf Life

2 years.

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

immediately.

6.5.Nature and Contents ofthe Container

EVICEL ®

consistsof apackage containing twoseparate vials(glass typeI) with rubber stoppers (type I),

eachcontaining 1ml, 2ml or 5mlofsolution(BAC2andThrombinrespectively), andan application

device package.

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

Thawing:

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

EVICEL ®

when applied byspraying. The application devicesare sterile aslong asthepackage is

unopenedand undamaged, and must only be usedonce.Noneedlesare involved in thepreparation of

EVICEL ®

for administration.

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.

Application byDripping

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.

SprayApplication

EVICEL ®

canbe sprayed usingpressurizedCO

2 orcompressedair.

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.

7.Manufactured by:

Omrix Biopharmaceuticals Ltd. (+logo)

MDA Blood Bank, Sheba Hospital, Ramat Gan

POB 888, Kiryat Ono, 55000, ISRAEL

8.Date ofRevision of the Text

February 2013

Art. 80FZ00M5-4

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

disconnects automatically.

5 If sprayingis required, connect the tubing tothepressure regulator. The applicator is now

ready for use.

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