CLEXANE MULTI DOSE

Main information

  • Trade name:
  • CLEXANE MULTI DOSE
  • Dosage:
  • 300/3 Mg/Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLEXANE MULTI DOSE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0540/097/003
  • Authorization date:
  • 19-06-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClexaneMultiDose300mg/3mlSolutionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

ActiveSubstance 3ml

EnoxaparinSodiumPh.Eur. 300.0mg

(equivalentto30,000IUanti-Xaactivity)

Every1mlcontains100mgEnoxaparinSodiumPh.Eur.(equivalentto10,000IUanti-Xaactivity).

Excipients

BenzylalcoholPh.Eur. 45.0mg

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

SolutionforInjection

Sterile,colourlesstoslightlyyellowsolutionforinjection.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Theprophylaxisofthromboembolicdisordersofvenousorigin,inparticularthosewhichmaybeassociatedwith

orthapaedicorgeneralsurgery

Theprophylaxisofvenousthromboembolisminmedicalpatientsbedriddenduetoacuteillnessesincluding

cardiacinsufficiency,respiratoryfailureorsevereinfections.

Thetreatmentofvenousthromboembolicdiseasepresentingwithdeepveinthrombosis,pulmonaryembolismor

both.

Thetreatmentofunstableanginaandnon-Q-wavemyocardialinfarction,administeredconcurrentlywithasprin.

TreatmentofacuteST-segmentElevationMyocardialInfraction(STEMI)includingpatientstobemanaged

medicallyorwithsubsequentPercutaneousCoronaryIntervention(PCI).

Thepreventionofthrombusformationintheextracorporealcirculationduringhaemodialysis.

4.2Posologyandmethodofadministration

Adults:

Prophylaxisofvenousthromboembolisminsurgicalpatients

Inpatientswithamoderateriskofvenousthromboembolism,therecommendeddosageofenoxaparinsodiumis20mg

(2,000IU)oncedailybysubcutaneousinjection.Inpatientsundergoingsurgery,theinitialdoseshouldbegiven

approximately2hourspre-operatively.

Inpatientswithahigherriskofthromboembolism,suchasinorthopaedicsurgery,therecommendeddosageof

enoxaparinsodiumgivenbysubcutaneousinjectionis40mg(4,000IU)oncedailywiththeinitialdoseadministered

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Enoxaparinsodiumtreatmentisusuallyprescribedforanaverageperiodof7to10days,oruntiltheriskof

thromboembolismhasdiminshed.

Longertreatmentdurationmaybeappropriateinsomepatientsfollowinghipreplacementandenoxaparinsodiummay

becontinuedforaslongasthereisariskofvenousthrombo-embolismanduntilthepatientisambulatory.

Continuedtherapywith40mgoncedailyfor3weeksfollowinginitialtherapyhasbeenproventobebeneficialin

patientsposthipreplacement.

ForspecialrecommendationsconcerningdosingintervalsforSpinal/EpiduralAnaesthesiaandPercutaneouscoronary

revascularisationprocedures:seePrecautions&Warningssection.

Prophylaxisofvenousthromboembolisminmedicalpatients

Therecommendeddoseofenoxaparinsodiumis40mgoncedailybysubcutaneousinjection.Treatmentwith

enoxaparinisprescribedforaminimumof6daysandcontinueduntilthefullreturntoambulation,foramaximumof

14days.Whereapatientisclinicallyadjudgedtobeatcontinuedsignificantriskforthromboemboliceventsbeyond

fourteendaysadecisiontoprolongprophylaxisshouldbemadeonanindividualbasis.

Treatmentofvenousthromboembolicdiseasepresentingwithdeepveinthrombosis,pulmonaryembolismorboth

Enoxoparinsodiumcanbeadministeredsubcutaneouslyeitherasasingleinjectionof1.5mg/kg(150IU/kg)orasa

twicedailyinjectionof1mg/kg(100IU/kg).Inpatientswithacomplicatedthromboembolicdisorder,adoseof

1mg/kg(100IU/kg)administeredtwicedailyisrecommended.

Enoxaparintreatmentisusuallyprescribedforatleast5daysanduntiladequateoralanticoagulationisestablished.

Treatmentofunstableanginaandnon-Q-wavemyocardialinfarction:

Therecommendeddose1mg/kg(100IU/kg)every12hoursbysubcutaneousinjection,administeredconcurrentlywith

oralaspirin(100to325mgoncedaily).Enoxaparintreatmentshouldbeprescribedforaminimumof2daysand

continueduntilclinicalstabilisation.Theusualdurationoftreatmentis2to8days.

Preventionofextracorporealthrombusformationduringhaemodialysis:

Adoseof1mg/kg(100IU/kg)introducedintothearteriallineatthebeginningofadialysissessionisusuallysufficient

fora4hourssession.Iffibrinringsarefound,suchasafteralongerthannormalsession,afurtherdoseof0.5to

1mg/kg(50to100IU/kg)maybegiven.Forpatientsatahighriskofhaemorrhagethedoseshouldbereducedto

0.5mg/kg(50IU/kg)fordoublevascularaccessor0.75mg/kg(75IU/kg)forsinglevascularaccess.

TreatmentofacuteST-segmentElevationMyocardialInfraction:

TherecommendeddoseofenoxaparinsodiumisasingleIVbolusof30mgplusa1mg/kgSCdosefollowedby

1mg/kgadministeredSCevery12hours(max100mgforthefirsttwodosesonly,followedby1mg/kgdosingforthe

remainingdoses).Fordosageinpatients75yearsofage,seesectiononElderly.

Whenadministeredinconjunctionwithathrombolytic(fibrinspecificornon-fibrinspecific)enoxaparinsodiumshould

begivenbetween15minutesbeforeand30minutesafterthestartoffibrinolytictherapy.Allpatientsshouldreceive

acetylsalicylicacid(ASA)assoonastheyareidentifiedashavingSTEMIandmaintainedunder(75to325mgonce

daily)unlesscontaindicated.

Therecommendeddurationofenoxaparinsodiumtreatmentis8daysoruntilhospitaldischarge,whichevercomes

first.

ForpatientsmanagedwithPercutaneousCoronaryIntervention(PCI:ifthelastenoxaparinsodiumSCadministration

wasgivenlessthan8hoursbeforeballooninflation,noadditionaldosingisneeded.IfthelastSCadministrationwas

givenmorethan8hoursbeforeballooninflation,anIVbolusof0.3mg/kgofenoxaparinsodiumshouldbe

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Elderly:

FortreatmentofST-segmentElevationMyocardialInfarctioninelderlypatients75yearsofage,donotuseaninitial

IVbolus.Initiatedosingwith0.75mg/kgSCevery12hours(maximum75mgforthefirsttwodosesonly,followedby

0.75mg/kgdosingfortheremainingdoses).

Forotherindications,nodoseadjustmentisnecessaryintheelderly,unlesskidneyfunctionisimpaired(seeWarnings

andPrecautions:HaemorrhageintheElderly,Pharmacokinetics:ElderlyandPosologyandMethodofAdministration:

Renalimpairment).

Paediatrics:

Notrecommended,asdosagenotestablished.

Themultiple-doseformulationcontainsbenzylalcoholasapreservativeandshouldnotbegiventoneonates.The

administrationofmedicinescontainingbenzylalcoholasapreservativetoprematureneonateshasbeenassociatedwith

afatal"GaspingSyndrome".

Renalimpairment:

(seeWarnings&Precautions:RenalimpairmentandPharmacokinetics:Renalimpairment).

Severerenalimpairment:

Adosageadjustmentisrequiredforpatientswithsevererenalimpairment(creatinineclearance<30ml/min),according

tothefollowingtables,sinceenoxaparinsodiumexposureissignificantlyincreasedinthispatientpopulation.

Thefollowingdosageadjustmentsarerecommendedfortherapeuticdosageranges:

Thefollowingdosageadjustmentarerecommendedforprophylacticdosageranges:

Therecommendeddosageadjustmentsdonotapplytothehaemodialysisindication.

ModerateandMildRenalImpairment:

Althoughnoadjustmentofthedoseisrecommendedinpatientswithmoderate(creatinineclearance30-50ml/min)and

mild(creatinineclearance50-80ml/min)renalimpairment,carefulclinicalmonitoringisadvised.

Hepaticimpairment

Intheabsenceofclinicalstudies,cautionshouldbeexercised.

Administration

StandardDosing Severerenalimpairment

1mg/kgSCtwicedaily 1mg/kgSConcedaily

1.5mg/kgSConcedaily 1mg/kgSConcedaily

30mg-singleIVbolusplusa1

mg/kgSCdosefollowedby1

mg/kgSCtwicedaily 30mg-singleIVbolusplusa1

mg/kgSCdosefollowedby1

mg/kgSConcedaily

Elderlypatients75yearsofage

(foracuteSTEMIindicationonly)

0.75mg/kgSCtwicedaily

withoutinitialbolus 1mg/kgSConcedailywithout

initialbolus

StandardDosing Severerenalimpairment

40mgoncedaily 20mgoncedaily

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Enoxaparinisadministeredbysubcutaneousinjectionforthepreventionortreatmentofdeepvenousthrombosis,for

thetreatmentofunstableanginaandnon-Q-wavemyocardialinfarctionandtreatmentofacuteST-segmentElevation

MyocardialInfraction.

IVBolusInjection:

ForacuteST-segmentElevationMyocardialInfraction,treatmentistobeinitiatedwithasingleIVbolusinjection

immediatelyfollowedbyasubcutaneousinjection.

ArteriallineInjection:

Itisadministeredthroughthearteriallineofadialysiscircuitforthepreventionofthrombusformationintheextra-

corporealcirculationduringhaemodialysis.

Itmustnotbeadministeredbytheintramuscularroute.

Theuseofatuberculinsyringeorequivalentisrecommendedwhenusingmultiple-dosevialstoassurewithdrawalof

theappropriatevolumeofdrug.

Subcutaneousinjectiontechnique:

Clexaneshouldbeadminsteredwhenthepatientislyingdown,bydeepsubcutaneousinjection.Theairbubbleshould

notbeexpelledfromthesyringebeforetheinjectionisgiventoavoidthelossofdrug.Theadministrationshouldbe

alternatedbetweentheleftandrightanterolateralorposterolateralabdominalwall.Thewholelengthoftheneedle

shouldbeintroducedverticallyintoaskinfoldheldbetweenthethumbandindexfinger.Theskinfoldshouldnotbe

releaseduntiltheinjectioniscomplete.Donotrubtheinjectionsiteafteradministration.

Intravenous(Bolus)InjectionTechnique(foracuteSTEMIindicationonly):

Forintravenousinjection,themulti-dosevialshouldbeused.Enoxaparinsoduimshouldbeadministeredthroughan

intravenousline.Itshouldnotbemixedorco-administeredwithothermedications.Toavoidthepossiblemixtureof

enoxaparinsodiumwiththeotherdrugs,theintravenousaccesschosenshouldbeflushedwithasufficientamountof

salineordextrosesolutionpriortoandfollowingtheintravenousbolusadministrationofenoxaparinsodiumtoclear

theportofdrug.Enoxaparinsodiummaybesafelyadministeredwithnormalsalinesolution(0.9%)or5%dextrosein

water.

4.3Contraindications

Contraindicatedinpatientswithacutebacterialendocarditis;activemajorbleedingdisordersandconditionswithahigh

riskofuncontrolledhaemorrhage,includingrecenthemorrhagicstrokeorsubduralhaematoma;thrombocytopeniain

patientswithapositivein-vitroaggregationtestinthepresenceofenoxaparin;injaundice;activegastricorduodenal

ulceration;hiatalulceration;threatenedabortion,orretinopathyHypersensitivitytoenoxaparin,heparinoritsderivates

includingotherLowMolecularWeightHeparins,Contraindicatedinpatientshypersensitivetobenzylalcohol.

4.4Specialwarningsandprecautionsforuse

General

Asdifferentlowmolecularweightheparinsmaynotbeequivalent,alternativeproductsshouldnotbesubstituted

duringacourseoftreatment.

Spinal/EpiduralAnesthesia

Aswithotheranti-coagulants,therehavebeencasesofneuraxialhaematomasreportedwiththeconcurrentuseof

enoxaparinandspinal/epiduralanaesthesiaresultinginlongtermorpermanentparalysis.Theseeventsarerarewith

enoxaparinsodiumdosageregimens40mgodorlower.Theriskisgreaterwithhigherenoxaparindosageregimens,

useofpost-operativeindwellingcathetersortheconcomitantuseofadditionaldrugsaffectinghaemostasissuchas

NSAIDs(seeInteractionswithothermedicamentsandotherformsofinteraction).

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Toreducethepotentialriskofbleedingassociatedwiththeconcurrentuseofenoxaparinandepiduralorspinal

anaesthesia/analgesia,thepharmacokineticprofileofthedrugshouldbeconsidered(seePharmacokineticproperties).

Placementandremovalofthecatheterisbestperformedwhentheanticoagulanteffectofenoxaparinislow.

Placementorremovalofacathetershouldbedelayedfor10-12hoursafteradministrationofDVTprophylacticdoses

ofenoxaparinsodium,whereaspatientsreceivinghigherdosesofenoxaparinsodium(1mg/kgtwicedailyor1.5mg/kg

oncedaily)willrequirelongerdelays(24hours).Thesubsequentenoxaparinsodiumdoseshouldbegivennosooner

thantwohoursaftercatheterremoval.

Shouldthephysiciandecidetoadministeranticoagulationinthecontextofepidural/spinalanaesthesia,extreme

vigilanceandfrequentmonitoringmustbeexercisedtodetectanysignsandsymptomsofneurologicalimpairment

suchasmidlinebackpain,sensoryandmotordeficits(numbnessorweaknessinthelowerlimbs),boweland/orbladder

dysfunction.Patientsshouldbeinstructedtoinformtheirphysicianimmediatelyiftheyexperienceanyoftheabove

signsorsymptoms.Ifsignsorsymptomsofspinalhaematomaaresuspectedurgentdiagnosisandtreatmentincluding

spinalcorddecompressionshouldbeinitiated.

Heparininducedthrombocytopenia

Enoxaparinistobeusedwithextremecautioninpatientswithahistoryofheparin-inducedthrombocytopeniawithor

withoutthrombosis.

Precutaneouscoronaryrevascularisationprocedures

Tominimizetheriskofbleedingfollowingthevascularinstrumentationduringthetreatmentofunstableangina,non-

Q-wavemyocardialinfarctionandacuteST-segmentelevationmyocardialinfarction,adherepreciselytotheintervals

recommendedbetweenClexaneinjectiondoses.ItisimportanttoachievehemostasisatthepuncturesiteafterPCI.In

caseaclosuredeviceused,thesheathcanberemovedimmediately.Ifmanualcompressionmethodisused,sheath

shouldberemoved6hoursafterlastafterthelastIV/SCenoxaparinsodiuminjection.Ifthetreatmentwithenoxaparin

sodiumistobecontinued,thenextscheduleddoseshouldbegivennosoonerthan6to8hoursaftersheathremoval.

Thesiteoftheprocedureshouldbeobservedforsignsofbleedingorhematomaformation.

PregnantWomenwithMechanicalProstheticHeartValves:

Theuseofclexaneforthromboprophylaxisinpregnantwomenwithmechanicalprostheticheartvalveshasnotbeen

adequatelystudied.Inaclinicalstudyofpregnantwomenwithmechanicalprostheticheartvalvesgivenenoxaparin

(1mg/kgbid)toreducetheriskofthromboembolism,2of8womendevelopedclotsresultinginblockageofthevalve

andleadingtomaternalandfoetaldeath.Therehavebeenisolatedpost-marketingreportsofvalvethrombosisin

pregnantwomenwithmechanicalprostheticheartvalveswhilereceivingenoxaparinforthromboprophylaxis.Pregnant

womenwithmechanicalprostheticheartvalvesmaybeathigherriskforthromboembolism(seemechanicalprosthetic

heartvalves).

LaboratoryTests

Atdosesusedforprophylaxisofvenousthromboembolism,enoxaparinsodiumdoesnotinfluencebleedingtimeand

globalbloodcoagulationtestssignificantly,nordoesitaffectplateletaggregationorbindingoffibrinogentoplatelets.

Athigherdoses,increasesinaPTT(activatedpartialthromboplastintime)andACT(activatedclottingtime)may

occur.IncreasesinaPTTandACTarenotlinearlycorrelatedwithincreasingenoxaparinsodiumantithrombotic

activityandthereforeareunsuitableandunreliableformonitoringenoxaparinsodiumactivity.

Donotadministerbytheintramuscularroute.

Haemorrhage

Aswithotheranticoagulants,bleedingmayoccuratanysite.Ifbleeding,theoriginofthehaemorrhageshouldbe

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Useinconditionswithincreasedpotentialforbleeding

Enoxaparininjection,aswithanyotheranticoagulanttherapy,shouldonlybeusedwithgreatcautioninconditions

withincreasedpotentialforbleeding,suchas:impairedhaemostasis,

historyofpepticulcerorbleeding,

recentischaemicstroke,

uncontrolledseverearterialhypertension,

severeliverorkidneydysfunction,

diabeticretinopathy,

recentophthalmologicorneurosurgeryortrauma

concomitantuseofmedicationsaffectinghemostasis(seeSection4.5).

MechanicalProstheticHeartValves:

Theuseofclexanehasnotbeenadequatelystudiedforthromboprophylaxisinpatientswithmechanicalprostheticheart

valves.Isolatedcasesofprostheticheartvalvethrombosishavebeenreportedinpatientswithmechanicalprosthetic

heartvalveswhohavereceivedenoxaparinforthromboprophylaxis.Confoundingfactors,includingunderlying

diseaseandinsufficientclinicaldata,limittheevaluationofthesecases.Someofthesecaseswerepregnantwomenin

whomthrombosisledtomaternalandfoetaldeath.Pregnantwomenwithmechanicalprostheticvalvesmaybeat

higherriskforthromboembolism(seepregnantwomenwithmechanicalprostheticheartvalves).

HaemorrhageintheElderly:

Noincreasedbleedingtendencyisobservedintheelderlywiththeprophylacticdosageranges.Elderlypatients

(especiallypatientseightyyearsofageandolder)maybeatanincreasedriskforbleedingcomplicationswiththe

therapeuticdosageranges.Carefulclinicalmonitoringisadvised(seePosologyandMethodofAdministration:Elderly

andPharmacokinetics:Elderly).

Renalimpairment

Inpatientswithrenalimpairment,thereisanincreaseinexposureofenoxaparinsodiumwhichincreasestheriskof

bleeding.Sinceexposureofenoxaparinsodiumissignificantlyincreasedinpatientswithsevererenalimpairment

(creatinineclearance <

30ml/min),adosageadjustmentisrecommendedfortherapeuticandprophylacticdosageranges.

Althoughnodoseadjustmentisrecommendedinpatientswithmoderate(creatinineclearance30-50ml/min)andmild

(creatinineclearance50-80ml/min)renalimpairment,carefulmonitoringisadvised(seeDosageandAdministration:

RenalimpairmentandPharmacokinetics:Renalimpairment).

LowWeight

Anincreaseinexposureofenoxaparinsodiumwithprophylacticdosages(non-weightadjusted)hasbeenobservedin

low-weightwomen( <

45kg)andlow-weightmen( <

57kg)whichmayleadtoahigherriskofbleeding.Therefore,

carefulclinicalmonitoringisadvisedinthesepatients(seePharmacokinetics:Weight).

Monitoringofplateletcounts

Asthereisariskofantibody-mediatedheparin-inducedthrombocytopeniaalsooccurringwithlowmolecularweight

heparins,regularplateletcountmonitoringshouldbeconsideredpriortoandduringtherapywiththeseagents.

Thrombocytopenia,shoulditoccur,usuallyappearsbetweenthe5thand21stdayfollowingthebeginningoftherapy

andmaybecomplicatedbythrombosis.Therefore,itisrecommendedthattheplateletcountsbemeasuredbeforethe

initiationoftherapywithenoxaparinandthenregularlythereafterduringthetreatment.

Iftheplateletcountissignificantlyreduced(30to50%oftheinitialvalue),orthrombosisoccurs,therapymustbe

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Hyperkalaemia

Heparincansuppressadrenalsecretionofaldosteroneleadingtohyperkalaemia,particularlyinpatientssuchasthose

withdiabetesmellitus,chronicrenalfailure,pre-existingmetabolicacidosis,araisedplasmapotassiumortaking

potassiumsparingdrugs.Theriskofhyperkalaemiaappearstoincreasewithdurationoftherapybutisusually

reversible.Plasmapotassiumshouldbemeasuredinpatientsatriskbeforestartingheparintherapyandinallpatient

treatedformorethan7days.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Itisrecommendedthatagentswhichaffecthaemostasisshouldbediscontinuedpriortoenoxaparintherapyunlesstheir

useisessential.Theseagentsincludemedicationssuchas:

Systemicsalicylates,acetylsalicylicacidandNSAIDSincludingketorolac,

Dextran40,ticlopidine,andclopidogrel.

Systemicglucocorticoids,

Thrombolyticsandanticoagulants,

Otheranti-plateletagentsincludingglycoproteinIIb/IIIaantagonists.

Ifthecombinationcannotbeavoided,enoxaparinshouldbeusedwithcarefulclinicalandlaboratorymonitoring.

4.6Fertility,pregnancyandlactation

Pregnancy

Thereisnoevidenceofteratogeniceffectinanimalstudies.Inhumans,thereisnoevidencethatenoxaparinsodium

crossestheplacentabarrierduringthesecondtrimesterofpregnancy.Thereisnoinformationavailableconcerningthe

firstandthirdtrimesters.

Astherearenoadequateandwellcontrolledstudiesinpregnantwomenandbecauseanimalstudiesarenotalways

predictiveofhumanresponse,thisdrugshouldbeusedduringpregnancyonlyifthephysicianhasestablishedaclear

need.

(SeeSection4.4:Pregnantwomenwithmechanicalprostheticheartvalves&Mechanicalprostheticheartvalves).

Lactation

Inlactatingrats,theconcentrationof 35

S-enoxaparinsodiumoritslabelledmetabolitesinmilkisverylow.

Itisnotknownwhetherunchangedexoxaparinsodiumisexcretedinhumanbreastmilk.Theoralabsorptionof

enoxaparinsodiumisunlikely.However,asaprecaution,lactatingmothersreceivingenoxaparinsodiumshouldbe

advisedtoavoidbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Enoxaparinhasnoeffectontheabilitytodriveandoperatemachines.

4.8Undesirableeffects

Haemorrhage

Bleedingmayoccurduringenoxaparintherapywithorwithoutthepresenceofassociatedriskfactorssuchas:organic

lesionsliabletobleed,invasiveproceduresortheuseofmedicationsaffectinghaemostasis(seeINTERACTION

section).Majorhaemorrhageincludingretroperitonealandintracranialbleedinghasbeenreported.Someofthesecases

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Therehavebeenreportsofneuraxialhaematomaswithconcurrentuseofenoxaparinandspinal/epiduralanaesthesiaor

spinalpuncture.Theseeventshaveresultedinvaryingdegreesofneurologicinjuriesincludinglong-termorpermanent

paralysis(seeSpecialwarningsandspecialprecautionsforuse).

Thrombocytopenia

Mild,transient,asymptomaticthrombocytopeniahasbeenreportedduringthefirstdaysoftherapy.Rarecasesof

immuno-allergicthrombocytopeniawiththrombosishavebeenreported.Insomecasesthrombosiswascomplicatedby

organinfarctionorlimbischaemia.(seeSpecialwarningsandspecialprecautionsforuse).

LocalReactions

Pain,haematomaandmildlocalirritationmayfollowthesubcutaneousinjectionofenoxaparin.Rarely,hard

inflammatorynoduleswhicharenotcysticenclosuresofenoxaparin,havebeenobservedattheinjectionsite.They

resolveafterafewdaysandshouldnotcausetreatmentdiscontinuation.

Exceptionalcasesofskinnecrosis,usuallyoccuringattheinjectionsitehavebeenreportedwithheparinsandlow

molecularweightheparins.Thesephenomenaareusuallyprecededbypurpuraorerythematousplaques,infiltratedand

painful.Treatmentwithenoxaparinmustbediscontinued.

Others

Althoughrare,cutaneous(bullouseruptions)orsystemicallergicreactionsincludinganaphylactic/anaphylactoid

reactionsmayoccur.Insomecasesdiscontinuationoftreatmentmaybenecessary.Veryrarecasesofhypersensitivity

cutaneousvasculitishavebeenreported.Asymptomaticandreversibleincreasesinplateletcountsandliverenzyme

levelshavebeenreported.

Casesofhyperkalaemiahavebeenreportedwithheparinsandlowmolecularweightheparins.

Heparinproductscancausehypoaldsteronism,whichmayresultinanincreaseinplasmapotassium.Rarely,clinically

significanthyperkalaemiamayoccurparticularlyinpatientswithchronicrenalfailureanddiabetesmellitus(See

PrecautionsandWarnings).

4.9Overdose

Orallyadministeredenoxaparinispoorlyabsorbedandevenlargeoraldosesshouldnotleadtoanyserious

consequences.Thismaybecheckedbyplasmaassaysofanti-Xaandanti-IIaactivities.

Accidentaloverdosefollowingparenteralorextracorporealadministrationmayproducehaemorrhagiccomplications.

Thesemaybelargelyneutralisedbyslowintravenousinjectionofprotamine.Thedoseofprotaminedependsonthe

doseofenoxaparinsodiuminjected:

1mgprotamineneutralizestheanticoagulanteffectof1mgofenoxaparinsodium,ifenoxaparinsodiumwas

administeredintheprevious8hours.

Aninfusionof0.5mgprotamineper1mgofenoxaparinsodiummaybeadministeredifenoxaparinsodiumwas

administeredgreaterthan8hoursprevioustotheprotamineadministration,orifithasbeendeterminedthata

seconddoseofprotamineisrequired.

After12hoursoftheenoxaparinsodiuminjection,protamineadministrationmaynotberequired.

However,evenwithhighdosesofprotamine,theanti-Xaactivityofenoxaparinisnevercompletelyneutralised

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Enoxaparinisalowmolecularweightheparin,withameanmolecularweightofapproximately4,500daltons.Inthein

vitropurifiedsystem,enoxaparinhasahighanti-Xaactivity(approximately100IU/mg)andlowanti-IIaoranti

thrombinactivity(approximately28IU/mg).Theseanticoagulantactivitiesaremediatedthroughanti-thrombinIII

(ATIII)resultinginanti-thromboticactivitiesinhumans.

Beyonditsanti-Xaactivity,furtheranti-thromoboticandanti-inflammatorypropertiesofenoxaparinhavebeen

identifiedinhealthysubjectsandpatientsaswellasinnon-clinicalmodels.TheseincludeATIII-dependentinhibition

ofothercoagulationfactorslikefactorVIIa,inductionofendogenousTissueFactorPathwayInhibitor(TFPI)release

aswellasareducedreleaseofvonWillebrandfactor(vWF)fromthevascularendotheliumintothebloodcirculation.

Thesefactorsareknowntocontributetotheoverallanti-thromboticeffectofenoxaparin.

Attherecommendeddoses,enoxaparindoesnotinfluencebleedingtimeandglobalbloodcoagulationtests

significantly,nordoesitaffectplateletaggregrationorbindingoffibrinogentoplatelets.

5.2Pharmacokineticproperties

Generalcharacteristics

Thepharmacokineticparametersofenoxaparinsodiumhavebeenstudiedmainlyintermsofthetimecourseofplasma

anti-Xaactivityandalsobyanti-IIaactivity,attherecommendeddosagerangesaftersingleandrepeatedsubcutaneous

administrationandaftersingleintravenousadministration.

Thequantitativedeterminationofanti-Xaandanti-IIapharmacokineticactivitieswasconductedbyvalidated

amidolyticmethodswithspecificsubstratesandanenoxaparinstandardcalibratedagainsttheinternationalstandard

forLMWHs(NIBSC).

Bioavailability:

Theabsolutebioavailabilityofenoxaparinsodiumaftersubcutaneousinjection,basedonanti-Xaactivity,iscloseto

100%.Injectionvolumeanddoseconcentrationovertherange100-200mg/mldoesnotaffectpharmacokinetic

parametersinhealthyvolunteers.

Absorption

Themeanmaximumplasmaanti-Xaactivityisobserved3to5hoursaftersubcutaneousinjectionandachieves

approximately0.2,0.4,and1.0and1.3anti-XaIU/mlfollowingsingle-subcutaneousadministrationof20,40mg,1

mg/kgand1.5mg/kgdoses,respectively.

Enoxaparinpharmacokineticsappeartobelinearovertherecommendeddosageranges.Intra-patientandinter-patient

variabilityislow.Afterrepeatedsubcutaneousadministrationof40mgoncedailyand1.5mg/kgoncedailyregimens

inhealthyvolunteers,thesteady-stateisreachedonday2withanaverageexposureratioabout15%higherthanaftera

singledose.Steady-stateenoxaparinactivitylevelsarewellpredictedbysingledosepharmacokinetics.

Afterrepeatedsubcutaneousadministrationofthe1mg/kgtwicedailyregimen,thesteadystateisreachedfromday3

to4withmeanexposureabout65%higherthanafterasingledoseandmeanpeakandtroughlevelsofabout1.2and

0.52IU/ml,respectively.Basedonenoxaparinsodiumpharmacokinetics,thisdifferenceinsteady-stateisexpected

withinthetherapeuticrange.

Plasmaanti-IIaactivityaftersubcutaneousadministrationisapproximatelyten-foldlowerthananti-Xaactivity.The

meanmaximumanti-IIaactivityisobservedapproximately3to4hoursfollowingsubcutaneousinjectionof40mg

(whileitisnotdetectableatthe20mgdoselevelwhenusingconventionalamidolyticmethod)andreaches0.13IU/ml

and0.19IU/mlfollowingrepeatedadministrationof1mg/kgtwicedailyand1.5mg/kgoncedaily,respectively.

Distribution:

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EliminationandMetabolism:

Enoxaparinsodiumisalowclearancedrugwithameananti-Xaplasmaclearanceof0.74L/haftera1.5mg/kg6-hour

intravenousinfusion.

Eliminationappearsmonophasicwithahalf-lifeofabout4hoursafterasingle-subcutaneousdosetoabout7hours

afterrepeateddosing.Theanti-Xaactivityis

measurableintheplasmaupto24hoursaftersubcutaneousinjectionof40mgenoxaparin.

Enoxaparinsodiumisprimarilymetabolisedintheliverbydesulfationand/ordepolymerisationtolowermolecular

weightspecieswithmuchreducedbiologicalpotency.Renalclearanceofactivefragmentsrepresentsabout10%ofthe

administereddoseandtotalrenalexcretionofactiveandnon-activefragments40%ofthedose.

Characteristicsinspecialpopulations:

Elderly:

Basedontheresultsofapopulationpharmacokineticanalysis,theenoxaparinsodiumkineticprofileisnotdifferentin

elderlysubjectscomparedtoyoungersubjectswhenrenalfunctionisnormal.Howeversincerenalfunctionisknown

todeclinewithage,elderlypatientsmayshowreducedeliminationofenoxaparinsodium(seePrecautions:

HaemorrhageintheElderly,DosageandAdministration:ElderlyandPharmacokinetics:Renalimpairment).

Renalimpairment:

5.3Preclinicalsafetydata

Nofurtherinformation

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzylalcohol

Waterforinjections

6.2Incompatibilities

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproductsexcept

thoselistedinsection6.6.

6.3Shelflife

Shelf-lifeofthemedicinalproductaspackagedforsale:2years.

In-useshelflifefollowingreconstitution:28days.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Donotrefrigerateorfreeze.

Forstorageconditionsofthereconstitutedmedicinalproductseesection6.3.

6.5Natureandcontentsofcontainer

TypeIclearglassvials(5ml)withchlorobutylrubberclosureandaluminiumplasticflip-offcaporalternatively,

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Seesection4.2Posologyandmethodofadministration.

Intravenous(Bolus)Injection(foracuteSTEMIindicationonly)

Enoxaparinsodiummaybesafelyadministeredwithnormalsalinesolution(0.9%)or5%dextrose.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Sanofi-AventisIrelandLtd.T/ASANOFI

CitywestBusinessCampus

Dublin24

Ireland.

8MARKETINGAUTHORISATIONNUMBER

PA540/97/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19 th

June2009

10DATEOFREVISIONOFTHETEXT

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