AGGRASTAT

Main information

  • Trade name:
  • AGGRASTAT Solution for Infusion 0.05mg/ ml Mg/ Ml
  • Dosage:
  • 0.05mg/ ml Mg/ Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AGGRASTAT Solution for Infusion 0.05mg/ml Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1720/001/001
  • Authorization date:
  • 18-11-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AGGRASTAT250micrograms/mlconcentrateforsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlofconcentrateforsolutionforinfusioncontains281microgramsoftirofibanhydrochloridemonohydratewhichis

equivalentto250microgramstirofiban.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion,50mlvial

Aclear,colourlessconcentratedsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Aggrastatisindicatedforthepreventionofearlymyocardialinfarctioninpatientspresentingwithunstableanginaor

non-Q-wavemyocardialinfarctionwiththelastepisodeofchestpainoccurringwithin12hoursandwithECGchanges

and/orelevatedcardiacenzymes.

PatientsmostlikelytobenefitfromAggrastattreatmentarethoseathighriskofdevelopingmyocardialinfarction

withinthefirst3-4daysafteronsetofacuteanginasymptomsincludingforinstancethosethatarelikelytoundergoan

earlyPTCA(seesections4.2and5.1).

Aggrastatisintendedforusewithacetylsalicylicacidandunfractionatedheparin.

4.2Posologyandmethodofadministration

Thisproductisforhospitaluseonly,byspecialistphysiciansexperiencedinthemanagementofacutecoronary

syndromes.

Aggrastatconcentrateforsolutionforinfusionmustbedilutedbeforeuse.

InpatientswhoaremanagedwithanearlyinvasivestrategyforNSTE-ACSandnotplannedtoundergoangiography

foratleast4hoursandupto48hoursafterdiagnosis,tirofibanisgivenintravenouslyataninitialinfusionrateof0.4

microgram/kg/minfor30minutes.Attheendoftheinitialinfusion,tirofibanshouldbecontinuedatamaintenance

infusionrateof0.1microgram/kg/min.Tirofibanshouldbegivenwithunfractionatedheparin(usuallyanintravenous

bolusof5,000units[U]simultaneouslywiththestartoftirofibantherapy,thenapproximately1,000Uperhour,

titratedonthebasisoftheactivatedthromboplastintime[APTT],whichshouldbeabouttwicethenormalvalue),ASA,

andoralantiplatelettherapy(see5.1'Pharmacodynamicproperties',PRISM-PLUSstudy),unlesscontra-indicated.

PatientsundergoingPCIdemonstratedclinicalefficacywithtreatmentwithtirofibanutilizinganinitialbolusof25

microgram/kggivenovera3minuteperiod,followedbyacontinuousinfusionatarateof0.15microgram/kg/minfor

18-24,andupto48hours.Tirofibantirofiban’shouldbeadministeredwithunfractionatedheparinandoralantiplatelet

therapy(see5.1‘Pharmacodynamicproperties’,ADVANCE–EVERESTstudy)unlesscontra-indicated.

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Patientswithseverekidneyfailure

Inseverekidneyfailure(creatinineclearance<30ml/min)thedosageofAggrastatshouldbereducedby50%(seealso

4.4‘Specialwarningsandprecautionsforuse’and5.2‘Pharmacokineticproperties’).

Thefollowingtableisprovidedasaguidetodosageadjustmentbyweight.

AggrastatConcentrateforSolutionforInfusionmustbedilutedtothesamestrengthas

AggrastatInjectionPremixed,asnotedunderInstructionsforUse.

StartanddurationoftherapywithAggrastat

InpatientswhoaremanagedwithanearlyinvasivestrategyforNSTE-ACSandnotplannedtoundergoangiography

foratleast4hoursandupto48hoursafterdiagnosis,Aggrastat0.4microgram/kg/minloadingdoseregimenshouldbe

initiatedupondiagnosis.Therecommendeddurationshouldbeatleast48hours.InfusionofAggrastatand

unfractionatedheparinmaybecontinuedduringcoronaryangiographyandshouldbemaintainedforatleast12hours

andnotmorethan24hoursafterangioplasty/atherectomy.Onceapatientisclinicallystableandnocoronary

interventionprocedureisplannedbythetreatingphysician,theinfusionshouldbediscontinued.Theentiredurationof

treatmentshouldnotexceed108hours.

IfthepatientdiagnosedwithNSTE-ACSandmanagedwithaninvasivestrategyundergoesangiographywithin4hours

afterthediagnosis,theAggrastat25microgram/kgdosebolusregimenshouldbeinitiatedatthestartofPCIwiththe

0.4microgram/kg/min

LoadingDoseRegimen

MostPatients 0.4microgram/kg/min

LoadingDoseRegimen

SevereKidneyFailure 25microgram/kgDoseBolus

Regimen

MostPatients

Patient

Weight(kg) 30min

Loading

Infusion

Rate

(ml/hr) Maintenance

Infusion

Rate

(ml/hr) 30min

Loading

Infusion

Rate

(ml/hr) Maintenance

Infusion

Rate

(ml/hr) Bolus

(ml) Maintenance

Infusion

Rate

(ml/hr)

30-37 16 4 8 2 17 6

38-45 20 5 10 3 21 7

46-54 24 6 12 3 25 9

55-62 28 7 14 4 29 11

63-70 32 8 16 4 33 12

71-79 36 9 18 5 38 14

80-87 40 10 20 5 42 15

88-95 44 11 22 6 46 16

96-104 48 12 24 6 50 18

105-112 52 13 26 7 54 20

113-120 56 14 28 7 58 21

121-128 60 15 30 8 62 22

129-137 64 16 32 8 67 24

138-145 68 17 34 9 71 25

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Concurrenttherapy(unfractionatedheparin,ASA)

Treatmentwithunfractionatedheparinisinitiatedwithani.v.bolusof5,000Uandthencontinuedwithamaintenance

infusionof1,000Uperhour.TheheparindosageistitratedtomaintainanAPTTofapproximatelytwicethenormal

value.

Unlesscontra-indicated,allpatientsshouldreceiveoralantiplateletagentsbeforethestartofAggrastat(see5.1

‘Pharmacodynamicproperties’,PRISM-PLUSstudy).Thismedicationshouldbecontinuedatleastforthedurationof

theinfusionofAggrastat.

Ifangioplasty(PTCA)isrequired,heparinshouldbestoppedafterPTCA,andthesheathsshouldbewithdrawnonce

coagulationhasreturnedtonormal,e.g.whentheactivatedclottingtime(ACT)islessthan180seconds(usually2-6

hoursafterdiscontinuationofheparin).

AGGRASTATSOLUTION

Instructionsforuse

Donotwithdrawsolutiondirectlyfromthecontainerwithasyringe.

DirectionsforuseofIntraVia containers

Toopen:TearfoiloverpouchorplasticdustcoverdownsideatslitandremoveIntraVia™container.Someopacityof

theplasticduetomoistureabsorptionduringthesterilisationprocessmaybeobserved.Thisisnormalanddoesnot

affectthesolutionqualityorsafety.Theopacitywilldiminishgradually.Checkforminuteleaksbysqueezinginner

bagfirmly.Ifleaksarefound,discardsolutionassterilitymaybeimpaired.

Donotuseunlesssolutionisclearandsealisintact.

Donotaddsupplementarymedicationorwithdrawsolutiondirectlyfromthebagwithasyringe.

CAUTION:Donotuseplasticcontainersinseriesconnections.Suchusecouldresultinairembolismduetoresidual

airbeingdrawnfromtheprimarycontainerbeforeadministrationofthefluidfromthesecondarycontaineris

completed.

Preparationforadministration

1.Suspendcontainerfromeyeletsupport.

2.Removeplasticprotectorfromoutletportatbottomofcontainer.

3.Attachadministrationset.Refertocompletedirectionsaccompanyingset.

Useaccordingtothedosagetableabove.

Wherethesolutionandcontainerpermit,parenteraldrugsshouldbeinspectedforvisibleparticlesordiscoloration

beforeuse.

Aggrastatshouldonlybegivenintravenouslyandmaybeadministeredwithunfractionatedheparinthroughthesame

infusiontube.

ItisrecommendedthatAggrastatbeadministeredwithacalibratedinfusionsetusingsterileequipment.

Careshouldbetakentoensurethatnoprolongationoftheinfusionoftheinitialdoseoccursandthatmiscalculationof

theinfusionratesforthemaintenancedoseonthebasisofthepatient’sweightisavoided.

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AGGRASTATCONCENTRATE

Instructionsforuse

AggrastatConcentratemustbedilutedbeforeuse:

Draw50mlfroma250mlcontainerofsterile0.9%salineor5%glucoseinwaterandreplacewith50ml

Aggrastat(fromone50mlpuncturevial)tomakeupaconcentrationof50microgram/ml.Mixwellbeforeuse.

Useaccordingtothedosagetableabove.

FORBOTHFORMULATIONS

Wherethesolutionandcontainerpermit,parenteraldrugsshouldbeinspectedforvisibleparticlesordiscoloration

beforeuse.

Aggrastatshouldonlybegivenintravenouslyandmaybeadministeredwithunfractionatedheparinthroughthesame

infusiontube.

ItisrecommendedthatAggrastatbeadministeredwithacalibratedinfusionsetusingsterileequipment.

Careshouldbetakentoensurethatnoprolongationoftheinfusionoftheinitialdoseoccursandthatmiscalculationof

theinfusionratesforthemaintenancedoseonthebasisofthepatient’sweightisavoided.

4.3Contraindications

Aggrastatiscontra-indicatedinpatientswhoarehypersensitivetotheactivesubstanceortoanyoftheexcipientsofthe

preparationorwhodevelopedthrombocytopeniaduringearlieruseofaGPIIb/IIIareceptorantagonist.

Sinceinhibitionofplateletaggregationincreasesthebleedingrisk,Aggrastatiscontra-indicatedinpatientswith:

Historyofstrokewithin30daysoranyhistoryofhaemorrhagicstroke.

Knownhistoryofintracranialdisease(e.g.neoplasm,arteriovenousmalformation,aneurysm).

Activeorrecent(withintheprevious30daysoftreatment)clinicallyrelevantbleeding(e.g.gastro-intestinal

bleeding).

Malignanthypertension.

Relevanttraumaormajorsurgicalinterventionwithinthepastsixweeks.

Thrombocytopenia(plateletcount<100,000/mm 3

),disordersofplateletfunction.

Clottingdisturbances(e.g.prothrombintime>1.3timesnormalorINR[InternationalNormalisedRatio]>1.5).

Severeliverfailure.

4.4Specialwarningsandprecautionsforuse

TheadministrationofAggrastatalonewithoutunfractionatedheparinisnotrecommended.

ThereislimitedexperiencewithconcomitantadministrationofAggrastatwithenoxaparin(seealso5.1

‘Pharmacodynamicproperties’and5.2‘Pharmacokineticproperties’).TheconcomitantadministrationofAggrastat

withenoxaparinisassociatedwithahigherfrequencyofcutaneousandoralbleedingevents,butnotinTIMIbleeds**,

whencomparedwiththeconcomitantadministrationofAggrastatandunfractionatedheparin.Anincreasedriskof

seriousbleedingeventsassociatedwiththeconcomitantadministrationofAggrastatandenoxaparincannotbe

excluded,particularlyinpatientsgivenadditionalunfractionatedheparininconjunctionwithangiographyand/orPCI.

TheefficacyofAggrastatincombinationwithenoxaparinhasnotbeenestablished.Thesafetyandefficacyof

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Thereisinsufficientexperiencewiththeuseoftirofibanhydrochlorideinthefollowingdiseasesandconditions,

however,anincreasedriskofbleedingissuspected.Therefore,tirofibanhydrochlorideisnotrecommendedin:

Traumaticorprotractedcardiopulmonaryresuscitation,organbiopsyorlithotripsywithinthepasttwoweeks

Severetraumaormajorsurgery>6weeksbut<3monthspreviously

Activepepticulcerwithinthepastthreemonths

Uncontrolledhypertension(>180/110mmHg)

Acutepericarditis

Activeoraknownhistoryofvasculitis

SuspectedaorticdissectionS

Haemorrhagicretinopathy

Occultbloodinthestoolorhaematuria

Thrombolytictherapy(see4.5‘Interactionwithothermedicinalproductsandotherformsofinteraction’).

Concurrentuseofdrugsthatincreasetheriskofbleedingtoarelevantdegree(see4.5‘Interactionwithother

medicinalproductsandotherformsofinteraction’).

Thereisnotherapeuticexperiencewithtirofibanhydrochlorideinpatientsforwhomthrombolytictherapyisindicated

(e.g.acutetransmuralmyocardialinfarctionwithnewpathologicalQ-wavesorelevatedST-segmentsorleftbundle-

branchblockintheECG).Consequently,theuseoftirofibanhydrochlorideisnotrecommendedinthese

circumstances.

Aggrastatinfusionshouldbestoppedimmediatelyifcircumstancesarisethatnecessitatethrombolytictherapy

(includingacuteocclusionduringPTCA)orifthepatientmustundergoanemergencycoronaryarterybypassgraft

(CABG)operationorrequiresanintra-aorticballoonpump.

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TIMImajorbleedsaredefinedasahaemoglobindropof>50g/lwithorwithoutanidentifiedsite,intracranial

haemorrhage,orcardiactamponade.TIMIminorbleedsaredefinedasahaemoglobindropof>30g/lby 50g/lwith

bleedingfromaknownsiteorspontaneousgrosshaematuria,haematemesis,orhaemoptysis.TIMI“lossnosite”is

definedasahaemoglobindrop>40g/lbut<50g/lwithoutanidentifiedbleedingsite.

ThereisnotherapeuticexperiencewithAggrastatinchildren,thus,theuseofAggrastatisnotrecommendedinthese

patients.

Otherprecautionarynotesandmeasures

Thereareinsufficientdataregardingthere-administrationofAggrastat.

PatientsshouldbecarefullymonitoredforbleedingduringtreatmentwithAggrastat.Iftreatmentofhaemorrhageis

necessary,discontinuationofAggrastatshouldbeconsidered(seealso4.9‘Overdose’).Incasesofmajoror

uncontrollablebleeding,tirofibanhydrochlorideshouldbediscontinuedimmediately.

Aggrastatshouldbeusedwithspecialcautioninthefollowingconditionsandpatientgroups:

Recentclinicallyrelevantbleeding(lessthanoneyear)

Punctureofanon-compressiblevesselwithin24hoursbeforeadministrationofAggrastat

Recentepiduralprocedure(includinglumbarpunctureandspinalanaesthesia)

Severeacuteorchronicheartfailure

Cardiogenicshock

Mildtomoderateliverinsufficiency

Plateletcount<150,000/mm 3

,knownhistoryofcoagulopathyorplateletfunctiondisturbanceorthrombocytopenia

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Specialcautionshouldbeusedduringconcurrentadministrationof,ticlopidine,clopidogrel,adenosine,dipyridamole,

sulfinpyrazone,andprostacyclin.

Efficacywithregardtodose

Theadministrationofa10microgram/kgbolusregimenoftirofibanfailedtoshownoninferiorityinclinicallyrelevant

endpointsat30dayscomparedtoabciximab(seealso5.1‘Pharmacodynamicproperties’).

Elderlypatients,femalepatients,andpatientswithlowbodyweight

Elderlyand/orfemalepatientshadahigherincidenceofbleedingcomplicationsthanyoungerormalepatients,

respectively.Patientswithalowbodyweighthadahigherincidenceofbleedingthanpatientswithahigherbody

weight.ForthesereasonsAggrastatshouldbeusedwithcautioninthesepatientsandtheheparineffectshouldbe

carefullymonitored.

Impairedrenalfunction

Thereisevidencefromclinicalstudiesthattheriskofbleedingincreaseswithdecreasingcreatinineclearanceand

hencealsoreducedplasmaclearanceoftirofiban.Patientswithdecreasedrenalfunction(creatinineclearance

<60ml/min)shouldthereforebecarefullymonitoredforbleedingduringtreatmentwithAggrastatandtheheparin

effectshouldbecarefullymonitored.InseverekidneyfailuretheAggrastatdosageshouldbereduced(seealso4.2

‘Posologyandmethodofadministration’).

Femoralarteryline

DuringtreatmentwithAggrastatthereisasignificantincreaseinbleedingrates,especiallyinthefemoralarteryarea,

wherethecathetersheathisintroduced.Careshouldbetakentoensurethatonlytheanteriorwallofthefemoralartery

ispunctured.Arterialsheathsmayberemovedwhencoagulationhasreturnedtonormal,e.g.whenactivatedclotting

time(ACT)islessthan180seconds,(usually2–6hoursafterdiscontinuationofheparin).

Afterremovaloftheintroducersheath,carefulhaemostasisshouldbeensuredundercloseobservation.

Generalnursingcare

Thenumberofvascularpunctures,andintramuscularinjectionsshouldbeminimisedduringthetreatmentwith

Aggrastat.I.V.accessshouldonlybeobtainedatcompressiblesitesofthebody.Allvascularpuncturesitesshouldbe

documentedandcloselymonitored.Theuseofurinarycatheters,nasotrachealintubationandnasogastrictubesshould

becriticallyconsidered.

Monitoringoflaboratoryvalues

Plateletcount,haemoglobinandhaematocritlevelsshouldbedeterminedbeforetreatmentwithAggrastataswellas

within2-6hoursafterstartoftherapywithAggrastatandatleastoncedailythereafterwhileontherapy(ormoreoften

ifthereisevidenceofamarkeddecrease).InpatientswhohavepreviouslyreceivedGPIIb/IIIareceptorantagonists

(crossreactivitycanoccur),theplateletcountshouldbemonitoredimmediatelye.g.withinthefirsthourof

administrationafterre-exposure(seealso4.8Undesirableeffects).Iftheplateletcountfallsbelow90,000/mm 3

furtherplateletcountsshouldbecarriedoutinordertoruleoutpseudothrombocytopenia.Ifthrombocytopeniais

confirmed,Aggrastatandheparinshouldbediscontinued.Patientsshouldbemonitoredforbleedingandtreatedif

necessary(seealso4.9‘Overdose’).

Inaddition,activatedthromboplastintime(APTT)shouldbedeterminedbeforetreatmentandtheanticoagulanteffects

ofheparinshouldbecarefullymonitoredbyrepeateddeterminationsofAPTTandthedoseshouldbeadjusted

accordingly(seealso4.2(‘Posologyandmethodofadministration’).Potentiallylife-threateningbleedingmayoccur

especiallywhenheparinisadministeredwithotherproductsaffectinghaemostasis,suchasGPIIb/IIIareceptor

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Theuseofseveralplateletaggregationinhibitorsincreasestheriskofbleeding,likewisetheircombinationwith

heparin,warfarinandthrombolytics.Clinicalandbiologicalparametersofhaemostasisshouldberegularlymonitored.

TheconcomitantadministrationofAggrastatandASA(acetylsalicyclicacidoraspirin)increasestheinhibitionof

plateletaggregationtoagreaterextentthanaspirinalone,asmeasuredbyexvivoAPD-inducedplateletaggregation

test.TheconcomitantadministrationofAggrastatandunfractionatedheparinincreasestheprolongationofthe

bleedingtimetoagreaterextentascomparedtounfractionatedheparinalone.

WiththeconcurrentuseofAggrastat,unfractionatedheparin,ASA,andclopidogreltherewasacomparableincidence

ofbleedingthanwhenonlyunfractionatedheparin,ASA,andclopidogrelwereusedtogether(seealso4.4‘Special

warningsandspecialprecautionsforuse’and4.8‘Undesirableeffects’).

Aggrastatprolongedbleedingtime;however,thecombinedadministrationofAggrastatandticlopidinedidnot

additionallyaffectbleedingtime.

ConcomitantuseofwarfarinwithAggrastatplusheparinwasassociatedwithanincreasedriskofbleeding.

Aggrastatisnotrecommendedinthrombolytictherapy-concurrentorlessthan48hoursbeforeadministrationof

tirofibanhydrochlorideorconcurrentuseofdrugsthatincreasetheriskofbleedingtoarelevantdegree(e.g.oral

anticoagulants,otherparenteralGPIIb/IIIainhibitors,dextransolutions).Thereisinsufficientexperiencewiththeuse

oftirofibanhydrochlorideintheseconditions;however,anincreasedriskofbleedingissuspected.

4.6Fertility,pregnancyandlactation

Pregnancy

Fortirofibanhydrochloride,noclinicaldataonexposedpregnanciesareavailable.Animalstudiesprovidelimited

informationwithrespecttoeffectsonpregnancy,embryonal/foetaldevelopment,parturition,andpostnatal

development.Aggrastatshouldnotbeusedduringpregnancyunlessclearlynecessary.

Breastfeeding

ItisnotknownwhetherAggrastatisexcretedinhumanmilk.Becauseofthepotentialforadverseeffectsonthe

nursinginfant,adecisionshouldbemadewhethertodiscontinuenursingordiscontinuethedrug,takingintoaccount

theimportanceofthedrugtothemother.

Fertility

Fertilityandreproductiveperformancewerenotaffectedinstudieswithmaleandfemaleratstreatedwithdifferent

dosesoftirofibanhydrochloride(seesection5.3).

However,animalstudiesareinsufficienttodrawconclusionswithrespecttoreproductivetoxicityinhumans.

4.7Effectsonabilitytodriveandusemachines

Notrelevant.

4.8Undesirableeffects

Bleeding

TheadverseeventcausallyrelatedtoAggrastattherapy(usedconcurrentlywithunfractionatedheparin,ASA,andoral

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AggrastatgivenwithunfractionatedheparinandASAwasassociatedwithgastro-intestinal,haemorrhoidalandpost-

operativebleeding,epistaxis,gumbleedsandsurfacedermatorrhagiaaswellasoozinghaemorrhage(haematoma)in

theareaofintravascularpuncturesites(e.g.incardiaccatheterexaminations)significantlymoreoftenthanwas

unfractionatedheparinandASAalone.

Withthe0.4microgram/kg/mininfusionregimen,therateofmajorbleedingcomplicationsislowandnotsignificantly

increased.

InthePRISM-PLUSstudy,theincidenceofTIMImajorbleedingwas1.4%fortirofibanincombinationwithheparin

and0.8%forheparinalone.TheincidenceofTIMIminorbleedingwas10.5%fortirofibanincombinationwith

heparinand8.0%forheparinalone.Thepercentageofpatientswhoreceivedatransfusionwas4.0%fortirofibanin

combinationwithheparinand2.8%forheparinalone.

Withthetirofiban25microgram/kgdosebolusregimen,datafromtheADVANCEstudysuggestthatthenumberof

bleedingeventsislowanddoesnotseemtobesignificantlyincreasedcomparedtoplacebo.TherewerenoTIMImajor

bleedingsandnotransfusionsineithergroup.TIMIminorbleedingwiththetirofiban25microgram/kgdosebolus

regimenwas4%ascomparedwith1%intheplaceboarmp=0.19).Therewerenocasesofseverethrombocytopenia

andtherateofmildthrombocytopeniawas1%withthetirofiban25microgram/kgdosebolusregimenand1%with

placebo.

Comparedwithabciximab,variousstudiesinvolvingover1200patientsshowedcomparablebleedingincidences

rangingfrom0%to0.5%withtirofibanvs.0%to3.2%forabciximabforTIMImajorbleedings,andnoincidenceof

thrombocytopenia.

Non-bleeding-associatedadversereactions

Themostcommonadversedrugreactions(incidenceover1%)associatedwithAggrastatgivenconcurrentlywith

heparin,apartfrombleeding,werenausea(1.7%),fever(1.5%)andheadache(1.1%);nausea,feverandheadache

occurredwithincidencesof1.4%,1.1%and1.2%,respectively,inthecontrolgroup.

Theincidenceofadversenon-bleeding-relatedeventswashigherinwomen(comparedtomen)andolderpatients

(comparedtoyoungerpatients).However,theincidencesofnon-bleeding-relatedadverseeventsinthesepatientswere

comparablefortheAggrastatwithheparin’groupandthe‘heparinalone’group.

[Common:(>1/100,<1/10)

Nervoussystemandpsychiatricdisorders:

Common:headache

Gastro-intestinaldisorders:

Common:nausea

Generaldisordersandadministrationsiteconditions:

Common:fever

Investigations

ThemostcommonchangesoflaboratoryparametersassociatedwithAggrastatrelatedtobleeding:reductionof

haemoglobinandhaematocritlevelsandanincreasedoccurrenceofoccultbloodinurineandfaeces.

OccasionallyduringAggrastattherapyanacutefallintheplateletcountorthrombocytopeniaoccurred.Thepercentage

ofpatientsinwhomtheplateletcountfelltobelow90,000/mm 3

was1.5%.Thepercentageofpatientsinwhomthe

plateletcountfelltolessthan50,000/mm 3

was0.3%.Thesedecreaseswerereversibleupondiscontinuationof

Aggrastat. Acuteandsevereplateletdecreaseshavebeenobservedinpatientswithnopriorhistoryof

thrombocytopeniauponre-administrationofGPIIb/IIIareceptorantagonists.

Thefollowingadditionaladversereactionshavebeenreportedinfrequentlyinpost-marketingexperience;theyare

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Bloodandlymphaticsystemdisorders:

Intracranialbleeding,retroperitonealbleeding,haemopericardium,pulmonary(alveolar)haemorrhage,andepidural

haematomainthespinalregion.Fatalbleedingshavebeenreportedrarely.

Acuteand/orsevere(<20,000/mm 3

)decreasesinplateletcountswhichmaybeassociatedwithchills,low-gradefever

orbleedingcomplications(see‘Investigations’above)

Immunesystemdisorders:

Severeallergicreactions(e.g.,bronchospasm,urticaria)includinganaphylacticreactions.Thereportedcaseshave

occurredduringinitialtreatment(alsoonthefirstday)andduringreadministrationoftirofiban.Somecaseshavebeen

associatedwithseverethrombocytopenia(plateletcounts<10,000/mm 3

4.9Overdose

Inadvertentoverdosagewithtirofibanhydrochlorideoccurredintheclinicalstudies,upto50microgram/kgasathree

minutebolusor1.2microgram/kg/minasaninitialinfusion.Overdosagewithupto1.47microgram/kg/minasa

maintenanceinfusionratehasalsooccurred.

a)Symptomsofoverdose

Thesymptomofoverdosemostcommonlyreportedwasbleeding,usuallymucosalbleedingandlocalisedbleedingat

thearterialpuncturesiteforcardiaccatheterisationbutalsosinglecasesofintracranialhaemorrhagesand

retroperitonealbleedings(seealso4.4and5.1,PRISM-PLUSstudy).

b)Measures

Overdosewithtirofibanhydrochlorideshouldbetreatedinaccordancewiththepatient’sconditionandtheattending

physician’sassessment.Iftreatmentofhaemorrhageisnecessary,theAggrastatinfusionshouldbediscontinued.

Transfusionsofbloodand/orthrombocytesshouldalsobeconsidered.Aggrastatcanberemovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATC-Code:B01AC17

Tirofibanhydrochloride(tirofiban)isanon-peptidalantagonistoftheGPIIb/IIIareceptor,animportantplateletsurface

receptorinvolvedinplateletaggregation.TirofibanpreventsfibrinogenfrombindingtotheGPIIb/IIIareceptor,thus

blockingplateletaggregation.

Tirofibanleadstoinhibitionofplateletfunction,evidencedbyitsabilitytoinhibitexvivoADP-inducedplatelet

aggregationandtoprolongbleedingtime(BT).Plateletfunctionreturnstobaselinewithineighthoursafter

discontinuation.

Theextentofthisinhibitionrunsparalleltothetirofibanplasmaconcentration.

Inthe0.1microgram/kgx30mininfusionregimenoftirofiban,inthepresenceofunfractionatedheparinandASA,

tirofibanproducedamorethan70%(median89%)inhibitionofexvivoADP-inducedplateletaggregationin93%of

thepatients,andaprolongationofthebleedingtimebyafactorof2.9duringinfusion.Inhibitionwasachievedrapidly

withthe30-minuteloadinginfusionandwasmaintainedoverthedurationoftheinfusion.

Thetirofiban25microgram/kgdosebolusregimen(followedby18-24hourmaintenanceinfusionof0.15

microgram/kg/min),inthepresenceofunfractionatedheparinandoralantiplatelettherapy,producedanaverageADP-

inducedinhibitionofmaximalaggregation15to60minutesafteronsetoftreatmentof92%to95%asmeasuredwith

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PRISM-PLUSstudy

Thedouble-blind,multicentre,controlledPRISM-PLUSstudycomparedtheefficacyoftirofibanandunfractionated

heparin(n=773)versusunfractionatedheparin(n=797)inpatientswithunstableangina(UA)oracutenon-Q-wave

myocardialinfarction(NQWMI)withprolongedrepetitiveanginalpainorpost-infarctionangina,accompaniedbynew

transientorpersistentST-Twavechangesorelevatedcardiacenzymes.

Patientswererandomisedtoeither

−tirofiban(30minuteloadinginfusionof0.4microgram/kg/minfollowedbyamaintenanceinfusionof0.10

microgram/kg/min)andheparin(bolusof5,000units(U)followedbyaninfusionof1,000U/hrtitratedtomaintainan

activatedpartialthromboplastintime(APTT)ofapproximatelytwotimescontrol),

−orheparinalone

AllpatientsreceivedASAunlesscontraindicatedstudydrugwasinitiatedwithin12hoursafterthelastanginalepisode.

Patientsweretreatedfor48hours,afterwhichtheyunderwentangiographyandpossiblyangioplasty/atherectomy,if

indicated,whiletirofibanwascontinued.Tirofibanwasinfusedforameanperiodof71.3hours.

Thecombinedprimarystudyend-pointwastheoccurrenceofrefractoryischaemia,myocardialinfarctionordeathat

sevendaysafterthestartoftirofibanhydrochloride.

At7days,theprimaryend-point,therewasa32%riskreduction(RR)(12.9%vs.17.9%)inthetirofibanhydrochloride

groupforthecombinedend-point(p=0.004):thisrepresentsapproximately50eventsavoidedfor1,000patientstreated.

After30daystheRRforthecompositeend-pointofdeath,MI,refractoryischaemicconditions,orreadmissionsfor

UAwas22%(18.5%vs.22.3%;p=0.029).Aftersixmonthstherelativeriskofcompositeofdeath,MI,refractory

ischaemicconditions,orreadmissionsforUAwasreducedby19%(27.7%vs.32.1%;p=0.024).

Regardingthe,compositeofdeathorMI,atsevendaysforthetirofibangrouptherewasa43%RR(4.9%vs.8.3%;

p=0.006);at30daystheRRwas30%(8.7%vs.11.9%;p=0.027)andat6monthstheRRwas23%(12.3%vs.15.3%;

p=0.063).

ThereductionofMIinpatientsreceivingtirofibanappearedearlyduringtreatment(withinthefirst48hours)andwas

maintainedthrough6months.Inthe30%ofpatientswhounderwentangioplasty/atherectomyduringinitial

hospitalisation,therewasa46%RR(8.8%vs.15.2%)fortheprimarycompositeendpointat30daysaswellasa43%

RR(5.9%vs.10.2%)fordeathorMI.

Basedonasafetystudy,theconcomitantadministrationoftirofiban(30minuteloadingdoseof[0.4

microgram/kg/min]followedbyamaintenanceinfusionof0.1microgram/kg/minforupto108hours)withenoxaparin

(n=315)wascomparedtotheconcomitantadministrationoftirofibanwithunfractionatedheparin(n=210)inpatients

presentingwithUAandNQWMI.Patientsintheenoxaparingroupreceiveda1.0milligram/kgsubcutaneousinjection

every12hoursforaperiodofatleast24hoursandamaximumdurationof96hours.Patientsrandomisedto

unfractionatedheparinreceiveda5000-unitintravenousbolusfollowedbyamaintenanceinfusionof1000unitsper

hourforatleast24hoursandamaximumdurationof108hours.ThetotalTIMIbleedratewas3.5%forthe

tirofiban/enoxaparingroupand4.8%forthetirofiban/unfractionatedheparingroup.Althoughtherewasasignificant

differenceintheratesofcutaneousbleedsbetweenthetwogroups(29.2%intheenoxaparinconvertedto

unfractionatedheparingroupand15.2%intheunfractionatedheparingroup),therewerenoTIMImajorbleeds(see

also4.4'Specialwarningsandprecautionsforuse')ineithergroup.Theefficacyoftirofibanincombinationwith

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ADVANCEstudy

TheADVANCEstudydeterminedthesafetyandefficacyofthetirofiban25microgram/kgdosebolusregimenas

comparedwithplaceboinpatientsundergoingelectiveorurgentPCIwhoexhibithigh-riskcharacteristicsincludingthe

presenceofatleastonecoronarynarrowing70%anddiabetes,needformulti-vesselintervention,orNSTE-ACS.All

patientsreceivedunfractionatedheparin,acetylsalicylicacid(ASA)andathienopyridineloadingdosefollowedby

maintenancetherapy.Atotalof202patientswererandomisedtoeitherTirofiban(25microgram/kgbolusIVover3

minutesfollowedbyacontinuousIVinfusionof0.15microgram/kg/minutefor24-48hours)orPlacebogiven

immediatelybeforePCI.

Theprimaryendpointwasacompositeofdeath,nonfatalMI,urgenttargetvesselrevascularization(uTVR),or

thromboticbailoutGPIIb/IIIainhibitortherapywithinamedianfollow-upof180daysaftertheindexprocedure.The

safetyendpointsofmajorandminorbleedingweredefinedaccordingtotheTIMIcriteria.

Intheintent-to-treatpopulation,thecumulativeincidenceoftheprimaryendpointwas35%and20%inplaceboand

tirofibangroups,respectively(hazardratio[HR]0.51[95%confidenceinterval(CI),0.29to0.88];p=0.01).As

comparedwithplacebo,therewasasignificantreductioninthecompositeofdeath,MI,oruTVRinthetirofibangroup

(31%vs.20%,HR,0.5795%CI,0.99–0.33];p=0.048.

EVERESTstudy

Therandomisedopen-labelEVERESTtrialcomparedtheupstream0.4microgram/kg/minloadingdoseregimen

initiatedinthecoronarycareunitwiththetirofiban25microgram/kgdosebolusregimenorabciximab0.25

milligram/kginitiated10minutespriortoPCI.AllpatientsadditionallyreceivedASAandathienopyridine.The93

enrolledNSTE-ACSpatientsunderwentangiographyandPCIasappropriate,within24-48hoursofadmission.

WithrespecttotheprimaryendpointsoftissuelevelperfusionandtroponinIrelease,theresultsofEVEREST

determinedsignificantlylowerratesofpost-PCITMPG0/1(6.2%vs.20%vs.35.5%,respectively;p=0.015),and

improvedpost-PCIMCEscoreindex(0.88±0.18vs.0.77±0.32vs.0.71±0.30,respectively;p<0.05).

Theincidenceofpost-proceduralcardiacTroponinI(cTnI)elevationwassignificantlyreducedinpatientstreatedwith

theupstreamtirofibanregimencomparedwithPCI25microgram/kgdosebolustirofibanorabciximab(9.4%vs.30%

vs.38.7%,respectively;p=0.018).ThecTnIlevelspost-PCIwerealsosignificantlydecreasedwiththeupstream

regimenoftirofibancomparedwithPCItirofiban(3.8±4.1vs.7.2±12;p=0.015)andabciximab(3.8±4.1vs.9±

13.8;p=0.0002).ThecomparisonbetweenthePCItirofiban25microgram/kgdosebolusandabciximabregimens

indicatednosignificantdifferencesintherateofTMPG0/1post-PCI(20%vs.35%;p=NS).

Severalfurthertrialswereconductedcomparingthe25microgram/kgdosebolusregimenwithabciximabinvolving

over1100NSTE-ACSpatientswhichshowednon-significantdifferenceswithrespecttothecompositeprimary

endpointofMACEat30daysrangingfrom5.8%to6.9%fortirofibanand7.1%to8.8%forabciximab.

Inonestudyusinga10microgram/kgbolusfollowedbya0.15microgram/kg/mininfusionoftirofiban(TARGET),

tirofibanfailedtodemonstratenoninferioritytoabciximab:theincidenceofthecompositeprimaryendpoint(death,

MI,oruTVRat30days)showedthatabciximabwassignificantlymoreeffectiveonclinicallyrelevantendpoints,with

7.6%inthetirofibanand6.0%intheabciximabgroup(p=0.038),whichwasmainlyduetoasignificantincreaseinthe

incidenceofMIat30days(respectively6.9%vs.5.4%;p=0.04).

5.2Pharmacokineticproperties

Distribution

Tirofibanisnotstronglyboundtoplasmaprotein,andproteinbindingisconcentration-independentintherangeof

0.01–25microgram/ml.Theunboundfractioninhumanplasmais35%.

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Biotransformation

Experimentswith 14

C-labelledtirofibanshowedtheradioactivityinurineandfaecestobeemittedchieflyby

unchangedtirofiban.Theradioactivityincirculatingplasmaoriginatesmainlyfromunchangedtirofiban(upto10

hoursafteradministration).Thesedatasuggestedlimitedmetabolisationoftirofiban.

Elimination

Afterintravenousadministrationof 14

C-labelledtirofibantohealthysubjects,66%oftheradioactivitywasrecoveredin

theurine,23%inthefaeces.Thetotalrecoveryofradioactivitywas91%.Renalandbiliaryexcretioncontribute

significantlytotheeliminationoftirofiban.

Inhealthysubjectstheplasmaclearanceoftirofibanisabout250ml/min.Renalclearanceis39–69%ofplasma

clearance.Thehalf-lifeisabout1.5hours.

Gender

Theplasmaclearanceoftirofibaninpatientswithcoronaryheartdiseaseissimilarinmenandwomen.

Elderlypatients

Theplasmaclearanceoftirofibanisabout25%lessinelderly(>65years)patientswithcoronaryheartdiseasein

comparisontoyounger(65years)patients.

Ethnicgroups

Nodifferencewasfoundintheplasmaclearancebetweenpatientsofdifferentethnicgroups.

CoronaryArteryDisease

InpatientswithunstableanginapectorisorNQWMItheplasmaclearancewasabout200ml/min,therenalclearance

39%oftheplasmaclearance.Thehalf-lifeisabouttwohours.

Impairedrenalfunction

Inclinicalstudies,patientswithdecreasedrenalfunctionshowedareducedplasmaclearanceoftirofibandependingon

thedegreeofimpairmentofcreatinineclearance.Inpatientswithacreatinineclearanceoflessthan30ml/min,

includinghaemodialysispatients,theplasmaclearanceoftirofibanisreducedtoaclinicallyrelevantextent(over50%)

(seesection4.2).Tirofibanisremovedbyhaemodialysis.

Liverfailure

Thereisnoevidenceofaclinicallysignificantreductionoftheplasmaclearanceoftirofibaninpatientswithmildto

moderateliverfailure.Nodataareavailableonpatientswithsevereliverfailure.

Effectsofotherdrugs

Theplasmaclearanceoftirofibaninpatientsreceivingoneofthefollowingdrugswascomparedtothatinpatientsnot

receivingthatdruginasub-setofpatients(n=762)inthePRISMstudy.Therewerenosubstantial(>15%)effectsof

thesedrugsontheplasmaclearanceoftirofiban:acebutolol,alprazolam,amlodipine,aspirinpreparations,atenolol,

bromazepam,captopril,diazepam,digoxin,diltiazem,docusatesodium,enalapril,furosemide,glibenclamide,

unfractionatedheparin,insulin,isosorbide,lorazepam,lovastatin,metoclopramide,metoprolol,morphine,nifedipine,

nitratepreparations,oxazepam,paracetamol,potassiumchloride,propranolol,ranitidine,simvastatin,sucralfateand

temazepam.

ThepharmacokineticsandpharmacodynamicsofAggrastatwereinvestigatedwhenconcomitantlyadministeredwith

enoxaparin(1milligram/kgsubcutaneouslyevery12hours)andcomparedwiththecombinationofAggrastatand

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5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicityandgenotoxicity.

Fertilityandreproductiveperformancewerenotaffectedinstudieswithmaleandfemaleratsgivenintravenousdoses

oftirofibanhydrochlorideupto5mg/kg/day.Thesedosagesareapproximately22-foldhigherthanthemaximum

recommendeddailydoseinhumans.

However,animalstudiesareinsufficienttodrawconclusionswithrespecttoreproductivetoxicityinhumans.

Tirofibancrossestheplacentainratsandrabbits.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride,sodiumcitratedihydrate,citricacidanhydrous,waterforinjection,hydrochloricacidand/orsodium

hydroxide(forpHadjustment).

6.2Incompatibilities

Incompatibilityhasbeenfoundwithdiazepam.Therefore,Aggrastatanddiazepamshouldnotbeadministeredinthe

sameintravenousline.

6.3Shelflife

3years.

Fromamicrobiologicalpointofviewthedilutedsolutionforinfusionshouldbeusedimmediately.Ifnotused

immediately,inusestorageconditionsaretheresponsibilityoftheuserandwouldnormallynotbelongerthan

24hoursat2-8 °

C,unlessreconstitutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotfreeze.Keepcontainerinoutercarton,toprotectfromlight.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

50mlTypeIglassvial.

6.6Specialprecautionsfordisposalandotherhandling

NoincompatibilitieshavebeenfoundwithAggrastatandthefollowingintravenousformulations:atropinesulfate,

dobutamine,dopamine,epinephrineHCl,furosemide,heparin,lidocaine,midazolamHCl,morphinesulfate,

nitroglycerin,potassiumchloride,propanololHClandfamotidineinjection.

Aggrastatconcentrateforsolutionforinfusionmustbedilutedbeforeuse.Seesection4.2.

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7MARKETINGAUTHORISATIONHOLDER

IrokoCardio(UK)Ltd

201Bishopgate

LondonEC2M3AF

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1720/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26July1999

Dateoflastrenewal: 14May2008

10DATEOFREVISIONOFTHETEXT

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