CLEXANE

Main information

  • Trade name:
  • CLEXANE Solution for Injection 100 Mg/Ml
  • Dosage:
  • 100 Mg/Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLEXANE Solution for Injection 100 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/064/001
  • Authorization date:
  • 21-12-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClexaneSyringes100mg/mlsolutionforinjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

ClexaneSyringes(100mg/ml)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

SolutionforInjection.

ProductimportedfromSpain:

Sterilepryogen-freesolutionforinjectioncontainedinready-to-usepre-filledsyringes.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Theprophylaxisofthromboembolicdisordersofvenousorigin,inparticularthosewhichmaybeassociatedwith

orthopaedicorgeneralsurgery.

Theprophylaxisofvenousthromboembolisminmedicalpatientsbedriddenduetoacuteillnessesincludingcardiac

insufficiency,respiratoryfailure,orsevereinfections.

Thetreatmentofvenousthromboembolicdiseasepresentingwithdeepveinthrombosis,pulmonaryembolismorboth.

Thetreatmentofunstableanginaandnon-Q-wavemyocardialinfarction,administeredconcurrentlywithaspirin.

TreatmentofacuteST-segmentElevationMyocardialInfarction(STEMI)includingpatientstobemanagedmedically

orwithsubsequentPercutaneousCoronaryIntervention(PCI).

Thepreventionofthrombusformationintheextracorporealcirculationduringhaemodialysis.

4.2Posologyandmethodofadministration

Adults:

Prophylaxisofvenousthromboembolisminsurgicalpatients

Inpatientswithamoderateriskofvenousthromboembolism,therecommendeddosageofenoxaparinsodiumis20mg

(2,000IU)oncedailybysubcutaneousinjection.Inpatientsundergoingsurgery,theinitialdoseshouldbegiven

approximately2hourspre-operatively.

Inpatientswithahigherriskofthromboembolism,suchasinorthopaedicsurgery,therecommendeddosageof

enoxaparinsodiumgivenbysubcutaneousinjectionis40mg(4,000IU)oncedailywiththeinitialdoseadministered

20mgInjection Enoxaparinsodium20mg(equivalentto2,000IUanti-Xa

activity)in0.2mlwaterforinjections

40mgInjection Enoxaparinsodium40mg(equivalentto4,000IUanti-Xa

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Enoxaparinsodiumtreatmentisusuallyprescribedforanaverageperiodof7to10days,oruntiltheriskof

thromboembolismhasdiminished.

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

fora4hoursession.Iffibrinringsarefound,suchasafteralongerthannormalsession,afurtherdoseof0.5to1mg/kg

(50to100IU/kg)maybegiven.Forpatientsatahighriskofhaemorrhagethedoseshouldbereducedto0.5mg/kg(50

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

TreatmentofacuteST-segmentElevationMyocardialInfarction:

TherecommendeddoseofenoxaparinsodiumisasingleIVbolusof30mgplusa1mg/kgSCdosefollowedby1

mg/kgadministeredSCevery12hours(max100mgforthefirsttwodosesonly,followedby1mg/kgdosingforthe

remainingdoses).Fordosageinpatients 75yearsofage,seesectiononElderly.

Whenadministeredinconjunctionwithathrombolytic(fibrinspecificornon-fibrinspecific)enoxaparinsodiumshould

begivenbetween15minutesbeforeand30minutesafterthestartoffibrinolytictherapy.Allpatientsshouldreceive

acetylsalicylicacid(ASA)assoonastheyareidentifiedashavingSTEMIandmaintainedunder(75to325mgonce

daily)unlesscontraindicated.

Therecommendeddurationofenoxaparinsodiumtreatmentis8daysoruntilhospitaldischarge,whichevercomes

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ForpatientsmanagedwithPercutaneousCoronaryIntervention(PCI:ifthelastenoxaparinsodiumSCadministration

wasgivenlessthat8hoursbeforeballooninflation,noadditionaldosingisneeded.IfthelastSCadministrationwas

givingmorethan8hoursbeforeballooninflation,anIVbolusof0.3mg/kgofenoxaparinsodiumshouldbe

administered.

Elderly:

FortreatmentofST-segmentElevationMyocardialInfarctioninelderlypatients 75yearsofage,donotuseaninitial

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

0.75mg/kgdosingfortheremainingdoses).

Forotherindications,nodoseadjustmentisnecessaryintheelderly,unlesskidneyfunctionisimpaired(seeWarnings

&Precautions:HaemorrhageintheElderly,Pharmacokinetics:ElderlyandPosologyandMethodofAdministration:

Renalimpairment).

Paediatrics:

Notrecommended,asdosagenotestablished.

Renalimpairment:

(seeWarnings&Precautions:RenalimpairmentandPharmacokinetics:Renalimpairment).

Severerenalimpairment:

Adosageadjustmentisrequiredforpatientswithsevererenalimpairment(creatinineclearance<30ml/min),according

tothefollowingtables,sinceenoxaparinsodiumexposureissignificantlyincreasedinthispatientpopulation.

Thefollowingdosageadjustmentsarerecommendedfortherapeuticdosageranges:

Thefollowingdosageadjustmentsarerecommendedforprophylacticdosageranges:

Therecommendeddosageadjustmentsdonotapplytothehaemodialysisindication.

ModerateandMildRenalImpairment:

Althoughnoadjustmentofthedoseisrecommendedinpatientswithmoderate(creatinineclearance30-50ml/min)and

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

StandardDosing Severerenalimpairment

1mg/kgSCtwicedaily 1mg/kgSConcedaily

1.5mg/kgSConcedaily 1mg/kgSConcedaily

30mg-singleIVbolusplusa1mg/kgSC

dosefollowedby1mg/kgSCtwicedaily 30mg-singleIVbolusplusa1mg/kgSC

dosefollowedby1mg/kgSConcedaily

Elderlypatients 75yearsofage(foracuteSTEMIindicationonly)

0.75mg/kgSCtwicedailywithoutinitial

bolus 1mg/kgSConcedailywithoutinitialbolus

StandardDosing Severerenalimpairment

1mg/kgtwicedaily 1mg/kgoncedaily

1.5mg/kgoncedaily 1mg/kgoncedaily

StandardDosing Severerenalimpairment

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Intheabsenceofclinicalstudies,cautionshouldbeexercised.

Administration

SubcutaneousInjection:

Enoxaparinisadministeredbysubcutaneousinjectionforthepreventionortreatmentofdeepvenousthrombosis,for

thetreatmentofunstableanginaandnon-Q-wavemyocardialinfarctionandtreatmentofacuteST-segmentElevation

MyocardialInfarction.

IVBolusInjection:

ForacuteST-segmentElevationMyocardialInfarction,treatmentistobeinitiatedwithasingleIVbolusinjection

immediatelyfollowedbyasubcutaneousinjection.

ArteriallineInjection:

Itisadministeredthroughthearteriallineofadialysiscircuitforthepreventionofthrombusformationintheextra-

corporealcirculationduringhaemodialysis.

Itmustnotbeadministeredbytheintramuscularroute.Thepre-filleddisposablesyringeisreadyforimmediateuse.

Subcutaneousinjectiontechnique:

Thepre-filleddisposablesyringeisreadyforimmediateuse.Clexaneshouldbeadministeredwhenthepatientislying

down,bydeepsubcutaneousinjection.Theairbubbleshouldnotbeexpelledfromthesyringebeforetheinjectionis

giventoavoidthelossofdrug.Theadministrationshouldbealternatedbetweentheleftandrightanterolateralor

posterolateralabdominalwall.Thewholelengthoftheneedleshouldbeintroducedverticallyintoaskinfoldheld

betweenthethumbandindexfinger.Theskinfoldshouldnotbereleaseduntiltheinjectioniscomplete.Donotrubthe

injectionsiteafteradministration.

4.3Contraindications

Contraindicatedinpatientswithacutebacterialendocarditis;activemajorbleedingdisordersandconditionswithahigh

riskofuncontrolledhaemorrhage,includingrecenthemorrhagicstrokeorsubduralhaematoma;thrombocytopeniain

patientswithapositivein-vitroaggregationtestinthepresenceofenoxaparin;injaundice;activegastricorduodenal

ulceration;hiatalulceration;threatenedabortion,orretinopathyHypersensitivitytoenoxaparin,heparinoritsderivates

includingotherLowMolecularWeightHeparins.

4.4Specialwarningsandprecautionsforuse

General

Asdifferentlowmolecularweightheparinsmaynotbeequivalent,alternativeproductsshouldnotbesubstituted

duringacourseoftreatment.

Heparininducedthrombocytopenia

Enoxaparinistobeusedwithextremecautioninpatientswithahistoryofheparin-inducedthrombocytopeniawithor

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Precutaneouscoronaryrevascularisationprocedures

Tominimizetheriskofbleedingfollowingthevascularinstrumentationduringthetreatmentofunstableangina,non-

Q-wavemyocardialinfarctionandacuteST-segmentelevationmyocardialinfarction,adherepreciselytotheintervals

recommendedbetweenClexaneinjectiondoses.ItisimportanttoachievehemostasisatthepuncturesiteafterPCI.In

caseaclosuredeviceused,thesheathcanberemovedimmediately.Ifmanualcompressionmethodisused,sheath

shouldberemoved6hoursafterlastafterthelastIV/SCenoxaparinsodiuminjection.Ifthetreatmentwithenoxaparin

sodiumistobecontinued,thenextscheduleddoseshouldbegivennosoonerthan6to8hoursaftersheathremoval.

Thesiteoftheprocedureshouldbeobservedforsignsofbleedingorhematomaformation.

LaboratoryTests

IncreasesinaPTT(activatedpartialthromboplastintime)andACT(activatedclottingtime)mayoccur.Increasesin

aPTTandACTarenotlinearlycorrelatedwithincreasingenoxaparinsodiumantithromboticactivityandthereforeare

unsuitableandunreliableformonitoringenoxaparinsodiumactivity.

Monitoringofplateletcounts

Asthereisariskofantibody-mediatedheparin-inducedthrombocytopeniaalsooccurringwithlowmolecularweight

heparins,regularplateletcountmonitoringshouldbeconsideredpriortoandduringtherapywiththeseagents.

Thrombocytopenia,shoulditoccur,usuallyappearsbetweenthe5thand21stdayfollowingthebeginningoftherapy

andmaybecomplicatedbythrombosis.Iftheplateletcountissignificantlyreduced(30to50%oftheinitialvalue),or

thrombosisoccurs,therapymustbediscontinuedimmediatelyandanalternativetherapyinitiated.

Haemorrhage

Aswithotheranticoagulants,bleedingmayoccuratanysite.Ifbleeding,theoriginofthehaemorrhageshouldbe

investigatedandappropriatetreatmentinstituted.

Useinconditionswithincreasedpotentialforbleeding

Enoxaparininjectionshouldonlybeusedwithgreatcautioninconditionswithincreasedpotentialforbleeding,such

as:impairedhaemostasis,historyofpepticulcerorbleeding,recentischaemicstroke,severearterialhypertension,

severeliverorkidneydysfunction,diabeticretinopathy,recentcerebralsurgeryortrauma.

Spinal/EpiduralAnesthesia

Aswithotheranti-coagulants,therehavebeencasesofneuraxialhaematomasreportedwiththeconcurrentuseof

enoxaparinandspinal/epiduralanaesthesiaresultinginlongtermorpermanentparalysis.Theseeventsarerarewith

enoxaparinsodiumdosageregimens40mgodorlower.Theriskisgreaterwithhigherenoxaparindosageregimens,

useofpost-operativeindwellingcathetersortheconcomitantuseofadditionaldrugsaffectinghaemostasissuchas

NSAIDs(seeInteractionswithothermedicamentsandotherformsofinteraction).Theriskalsoappearstobeincreased

bytraumaticorrepeatedneuraxialpuncture.

Toreducethepotentialriskofbleedingassociatedwiththeconcurrentuseofenoxaparinandepiduralorspinal

anaesthesia/analgesia,thepharmacokineticprofileofthedrugshouldbeconsidered(seePharmacokineticproperties).

Placementandremovalofthecatheterisbestperformedwhentheanticoagulanteffectofenoxaparinislow.

Placementorremovalofacathetershouldbedelayedfor10-12hoursafteradministrationofDVTprophylacticdoses

ofenoxaparinsodium,whereaspatientsreceivinghigherdosesofenoxaparinsodium(1mg/kgtwicedaily)willrequire

longerdelays(24hours).Thesubsequentenoxaparinsodiumdoseshouldbegivennosoonerthantwohoursafter

catheterremoval.

Shouldthephysiciandecidetoadministeranticoagulationinthecontextofepidural/spinalanaesthesia,extreme

vigilanceandfrequentmonitoringmustbeexercisedtodetectanysignsandsymptomsofneurologicalimpairment

suchasmidlinebackpain,sensoryandmotordeficits(numbnessorweaknessinthelowerlimbs),boweland/orbladder

dysfunction.Patientsshouldbeinstructedtoinformtheirphysicianimmediatelyiftheyexperienceanyoftheabove

signsorsymptoms.Ifsignsorsymptomsofspinalhaematomaaresuspectedurgentdiagnosisandtreatmentincluding

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PregnantWomenwithMechanicalProstheticHeartValves:

Theuseofclexaneforthromboprophylaxisinpregnantwomenwithmechanicalprostheticheartvalveshasnotbeen

adequatelystudied.Inaclinicalstudyofpregnantwomenwithmechanicalprostheticheartvalvesgivenenoxaparin

(1mg/kgbid)toreducetheriskofthromboembolism,2of8womendevelopedclotsresultinginblockageofthevalve

andleadingtomaternalandfoetaldeath.Therehavebeenisolatedpost-marketingreportsofvalvethrombosisin

pregnantwomenwithmechanicalprostheticheartvalveswhilereceivingenoxaparinforthromboprophylaxis.Pregnant

womenwithmechanicalprostheticheartvalvesmaybeathigherriskforthromboembolism(seemechanicalprosthetic

heartvalves).

MechanicalProstheticHeartValves:

Theuseofclexanehasnotbeenadequatelystudiedforthromboprophylaxisinpatientswithmechanicalprostheticheart

valves.Isolatedcasesofprostheticheartvalvethrombosishavebeenreportedinpatientswithmechanicalprosthetic

heartvalveswhohavereceivedenoxaparinforthromboprophylaxis.Confoundingfactors,includingunderlyingdisease

andinsufficientclinicaldata,limittheevaluationofthesecases.Someofthesecaseswerepregnantwomeninwhom

thrombosisledtomaternalandfoetaldeath.Pregnantwomenwithmechanicalprostheticvalvesmaybeathigherrisk

forthromboembolism(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).

Hyperkalaemia

Heparincansuppressadrenalsecretionofaldosteroneleadingtohyperkalaemia,particularlyinpatientssuchasthose

withdiabetesmellitus,chronicrenalfailure,pre-existingmetabolicacidosis,araisedplasmapotassiumortaking

potassiumsparingdrugs.Theriskofhyperkalaemiaappearstoincreasewithdurationoftherapybutisusually

reversible.Plasmapotassiumshouldbemeasuredinpatientsatriskbeforestartingheparintherapyandinallpatient

treatedformorethan7days.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Itisrecommendedthatagentswhichaffecthaemostasisshouldbediscontinuedpriortoenoxaparintherapyunlesstheir

useisessential,suchas:systemicsalicylates,acetylsalicylicacidandNSAIDS,Dextran40,ticlopidine,and

clopidogrel.Systemicglucocorticoids,thrombolytics,anticoagulantsandotheranti-plateletagentsincluding

glycoproteinIIb/IIIaantagonists.Ifthecombinationcannotbeavoided,enoxaparinshouldbeusedwithcarefulclinical

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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).Theoriginofthebleedingshouldbeinvestigatedandappropriatetreatmentinstituted.Majorhaemorrhage

includingretroperitonealandintracranialbleedinghasbeenreported.Someofthesecaseshavebeenlethal.

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.

Exceptionalcasesofskinnecrosisattheinjectionsitehavebeenreportedwithheparinsandlowmolecularweight

heparins.Thesephenomenaareusuallyprecededbypurpuraorerythematousplaques,infiltratedandpainful.

Treatmentwithenoxaparinmustbediscontinued.

Others

Although rare, cutaneous (bullous eruptions) or systemic allergic reactions may occur including

anaphylactic/anaphylactoidreactionsmayoccur.Insomecasesdiscontinuationoftreatmentmaybenecessary.

Asymptomaticandreversibleincreasesinplateletcountsandliverenzymelevelshavebeenreported.

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Heparinproductscancausehypoaldsteronism,whichmayresultinanincreaseinplasmapotassium.Rarely,clinically

significanthyperkalaemiamayoccurparticularlyinpatientswithchronicrenalfailureanddiabetesmellitus(See

PrecautionsandWarnings).

4.9Overdose

Orallyadministeredenoxaparinispoorlyabsorbedandevenlargeoraldosesshouldnotleadtoanyserious

consequences.Thismaybecheckedbyplasmaassaysofanti-Xaandanti-IIaactivities.

Accidentaloverdosefollowingparenteraladministrationmayproducehaemorrhagiccomplications.Thesemaybe

largelyneutralisedbyslowintravenousinjectionofprotaminesulphateorhydrochloride.

Thedoseofprotamineshouldbeequaltothedoseofenoxaparininjected,thatis,100anti-heparinunitsofprotamine

shouldneutralisetheanti-IIaactivitygeneratedby1mg(100IU)ofenoxaparin.

However,evenwithhighdosesofprotamine,theanti-Xaactivityofenoxaparinisnevercompletelyneutralised

(maximumapproximately60%).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Enoxaparinisalowmolecularweightheparin,withameanmolecularweightofapproximately4,500daltons.Inthein

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

thrombinactivity(approximately28IU/mg).

Attherecommendeddoses,enoxaparindoesnotinfluencebleedingtimeandglobalbloodcoagulationtests

significantly,nordoesitaffectplateletaggregationorbindingoffibrinogentoplatelets.

5.2Pharmacokineticproperties

Generalcharacteristics

Thepharmacokineticparametersofenoxaparinsodiumhavebeenstudiedmainlyintermsofthetimecourseofplasma

anti-Xaactivityandalsobyanti-IIaactivity,attherecommendeddosagerangesaftersingleandrepeatedsubcutaneous

administrationandaftersingleintravenousadministration.

Thequantitativedeterminationofanti-Xaandanti-IIapharmacokineticactivitieswasconductedbyvalidated

amidolyticmethodswithspecificsubstratesandanenoxaparinstandardcalibratedagainsttheinternationalstandardfor

LMWHs(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/kgoncedailyregimensin

healthyvolunteers,thesteady-stateisreachedonday2withanaverageexposureratioabout15%higherthanaftera

singledose.Steady-stateenoxaparinactivitylevelsarewellpredictedbysingledosepharmacokinetics.

Afterrepeatedsubcutaneousadministrationofthe1mg/kgtwicedailyregimen,thesteadystateisreachedfromday3

to4withmeanexposureabout65%higherthanafterasingledoseandmeanpeakandtroughlevelsofabout1.2and

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Basedonenoxaparinsodiumpharmacokinetics,thisdifferenceinsteady-stateisexpectedwithinthetherapeuticrange.

Plasmaanti-IIaactivityaftersubcutaneousadministrationisapproximatelyten-foldlowerthananti-Xaactivity.The

meanmaximumanti-IIaactivityisobservedapproximately3to4hoursfollowingsubcutaneousinjectionof40mg

(whileitisnotdetectableatthe20mgdoselevelwhenusingconventionalamidolyticmethod)andreaches0.13IU/ml

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

Distribution:

Thevolumeofdistributionofenoxaparinanti-Xaactivityisabout5litresandisclosetothebloodvolume.

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.Howeversincerenalfunctionisknownto

declinewithage,elderlypatientsmayshowreducedeliminationofenoxaparinsodium(seePrecautions:Haemorrhage

intheElderly,DosageandAdministration:ElderlyandPharmacokinetics:Renalimpairment).

Renalimpairment:

Alinearrelationshipexistsbetweenanti-Xaplasmaclearanceandcreatinineclearanceatsteady-statehasbeen

observed,whichindicatesdecreasedclearanceofenoxaparinsodiuminpatientswithreducedrenalfunction.Anti-Xa

exposurerepresentedbyAUC,atsteady-stateismarginallyincreasedinmild(creatinineclearance50-80ml/min)and

moderate(creatinineclearance30-50ml/min)renalimpairmentafterrepeatedsubcutaneous40mgoncedailydoses.In

patientswithsevererenalimpairment(creatinineclearance<30ml/min),theAUCatsteadystateissignificantly

increasedonaverageby65%afterrepeatedsubcutaneous40mgoncedailydoses(seePrecautions:Renalimpairment

andDosageandAdministration:Renalimpairment).

Weight

Afterrepeatedsubcutaneous1.5mg/kgoncedailydosing,meanAUCofanti-Xaactivityismarginallyhigheratsteady

stateinobesehealthyvolunteers(BMI30-48kg/m 2

)comparedtonon-obesecontrolsubjects,whileAmaxisnot

increased.Thereisalowerweight-adjustedclearanceinobesesubjectswithsubcutaneousdosing.

Whennon-weightadjusteddosingwasadministered,itwasfoundafterasinglesubcutaneous40mgdose,thatanti-Xa

exposureis50%higherinlow-weightwomen(<45kg)and27%higherinlow-weightmen(<57kg)whencomparedto

normalweightcontrolsubjects(seePrecautions:LowWeight).

Haemodialysis:

Inasinglestudy,eliminationrateappearedsimilarbutAUCwastwofoldhigherthancontrolpopulation,afterasingle

Irish Medicines Board

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5.3Preclinicalsafetydata

Nofurtherinformation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

WaterforInjections

6.2Incompatibilities

Intheabsenceofcompatabilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Donotrefrigerateorfreeze.

6.5Natureandcontentsofcontainer

HypakSCFpre-filledsyringes(BectonDickinson)inpacksof10,containing0.2mlor0.4mlofsolution.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

See"Posologyandmethodofadministration".

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:21stDecember2006

DateofLastRenewal:21stDecember2011

10DATEOFREVISIONOFTHETEXT

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Date Printed 30/03/2012 CRN 2109264 page number: 11