Asasantin ® SR dipyridamole and aspirin. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. You are allergic (hypersensitive) to listed in this leaflet, please tell your doctor or ASASANTINRetard200mg/25mgModifiedReleaseHardCapsulesEachcapsulecontainsdipyridamole200mgandacetylsalicylicacid(aspirin)25mg.Hardcapsulecontainingacetylsalicylicacidinstandardreleaseformanddipyridamoleinmodifiedreleaseform.CapsulesconsistingofaredcapandanivorybodyimprintedwiththeCompanylogoandthefigure‘01A’.Secondarypreventionofischaemicstrokeandtransientischaemicattacks.Therecommendeddoseisonecapsuletwicedaily,usuallyoneinthemorningandoneintheeveningpreferablywithThecapsulesshouldbeswallowedwholewithoutchewingtogetherwithaglassofwater.ASASANTINRetardisnotindicatedforuseinchildrenandyoungpeoplelessthan16yearsofage(see“SpecialIntheeventofintolerableheadachesduringtreatmentinitiation,switchtoonecapsuleatbedtimeandlow-doseacetylsalicylicacid(ASA)inthemorning.Becausetherearenooutcomedatawiththisregimenandheadachesbecomelessofaproblemastreatmentcontinues,patientsshouldreturntotheusualregimenassoonaspossible,usuallywithinoneHypersensitivitytoanycomponentoftheproductorsalicylates.Patientswithactivegastricorduodenalulcersorbleedingdisorders.IncertainrarehereditaryconditionstheproductiscontraindicatedowingtothepresenceofcertainexcipientsintheDuetotheriskofbleeding,aswithotherantiplateletagents,ASASANTINshouldbeusedwithcautioninpatientsatincreasedbleedingriskandpatientsshouldbefollowedcarefullyforanysignsofbleeding,includingoccultbleeding(seeCautionshouldbeadvisedinpatientsreceivingconcomitantmedicationwhichmayincreasetheriskofbleeding,suchasanticoagulants,anti-plateletagents,selectiveserotoninreuptakeinhibitors(SSRIs),oranagrelide(seesection4.5).Amongotherpropertiesdipyridamoleactsasavasodilator.Dipyridamoleshouldbeusedwithcautioninpatientswithseverecoronaryarterydisease,includingunstableanginaand/orrecentmyocardialinfarction,leftventricularoutflowobstruction,orhaemodynamicinstability(e.g.decompensatedheartfailure).ThedoseofacetylsalicylicacidinASASANTINRetardhasnotbeenstudiedinsecondarypreventionofmyocardialInpatientswithmyastheniagravisreadjustmentoftherapymaybenecessaryafterchangesindipyridamoledosage(seeAsmallnumberofcaseshavebeenreportedinwhichunconjugateddipyridamolewasshowntobeincorporatedintogallstonestoavariableextent(upto70%bydryweightofstone).Thesepatientswereallelderly,hadevidenceofascendingcholangitisandhadbeentreatedwithoraldipyridamoleforanumberofyears.Thereisnoevidencethatdipyridamolewastheinitiatingfactorincausinggallstonestoforminthesepatients.ItispossiblethatbacterialdeglucuronidationofconjugateddipyridamoleinbilemaybethemechanismresponsibleforthepresenceofdipyridamoleHeadacheormigraine-likeheadachewhichmayoccurespeciallyatthebeginningofASASANTINtherapyshouldnotbetreatedwithanalgesicdosesofacetylsalicylicacid(seesection4.2).Inaddition,cautionisadvisedinpatientshypersensitivetonon-steroidalanti-inflammatorydrugs(NSAIDs).Duetotheacetylsalicylicacidcomponent,ASASANTINRetardshouldbeusedwithcautioninpatientswithasthma,allergicrhinitis,nasalpolyps,chronicorrecurringgastricorduodenalcomplaints,impairedrenalorhepaticfunction(seesection5.2)orglucose-6-phosphatedehydrogenasedeficiency.ASASANTINRetardisnotindicatedforuseinchildrenandyoungpeoplelessthan16yearsofage.ThereisariskofPatientsbeingtreatedwithregularoraldosesofASASANTINRetardshouldnotreceiveadditionalintravenousdipyridamole.Clinicalexperiencesuggeststhatpatientsbeingtreatedwithoraldipyridamolewhoalsorequirepharmacologicalstresstestingwithintravenousdipyridamole,shoulddiscontinuedrugscontainingoraldipyridamoletwenty-fourhourspriortobeingtreatedwithintravenousdipyridamole.Intakeoforaldipyridamoletwenty-fourhourspriortostresstestingwithintravenousdipyridamolemayimpairthesensitivityofthetest.maximumrecommendeddailydose.Patientswithrarehereditaryproblemsoffructoseintoleranceand/orgalactoseintolerancee.g.galactosaemiashouldnottakethismedicine.GastrointestinalsideeffectsincreasewhenacetylsalicylicacidisadministeredconcomitantlywithNSAIDs,corticosteroidsTheconcomitantadministrationofibuprofenbutnotcertainotherNSAIDsorparacetamol,inpatientswithincreasedcardiovascularriskmaylimitthebeneficialcardiovasculareffectsofacetylsalicylicacid.Experimentaldatasuggestthatibuprofenmayinhibittheeffectoflowdoseaspirinonplateletaggregationwhentheyaredosedconcomitantly.However,thelimitationsofthesedataandtheuncertaintiesregardingextrapolationofexvivodatatotheclinicalsituationimplythatnofirmconclusionscanbemadeforregularibuprofenuse,andnoclinicallyrelevanteffectisconsideredtobelikelyforWhendipyridamoleisusedincombinationwithanysubstancesimpactingcoagulationsuchasanticoagulantsandantiplatelets,thesafetyprofileforthesemedicationsmustbeobserved.Acetylsalicylicacidhasbeenshown,whengivenwithanticoagulants,antiplateletdrugs,selectiveserotoninreuptakeinhibitors(SSRIs),oranagrelidetoincreasetheriskofbleeding.TheadditionofdipyridamoletoacetylsalicylicaciddoesWhendipyridamolewasadministeredconcomitantlywithwarfarin,bleedingwasnogreaterinfrequencyorseveritythanAcetylsalicylicacidhasbeenshowntoenhancetheeffectofvalproicacidandphenytoinwhichmayresultinanincreasedDipyridamoleincreasestheplasmalevelsandcardiovasculareffectsofadenosine.Adjustmentofadenosinedosageshouldthereforebeconsideredifusewithdipyridamoleisunavoidable.Dipyridamolemayincreasethehypotensiveeffectofdrugs,whichreducebloodpressure.DipyridamolemaycounteracttheanticholinesteraseeffectofcholinesteraseinhibitorstherebypotentiallyaggravatingTheeffectofhypoglycaemicagentsandthetoxicityofmethotrexatemaybeincreasedbytheconcomitantadministrationAcetylsalicylicacidmaydecreasethenatriureticeffectofspironolactoneandinhibittheeffectofuricosuricagents(e.g.Thereisinsufficientevidenceofsafetyinhumanpregnancyregardingdipyridamoleandacetylsalicylicacidatlowdose.ASASANTINRetardshouldonlybeadministeredduringfirstandsecondtrimesterofpregnancywhenthepotentialbenefitsforthemotheroutweighthepossiblerisksforthefoetus.ASASANTINRetardiscontraindicatedinthethirdtrimesterofpregnancy.Dipyridamoleandsalicylatesareexcretedinbreastmilk(seesection5.2).ASASANTINRetardshouldonlybeusedinbreast-feedingwomenwhenthepotentialbenefitsforthemotheroutweighNostudiesontheeffectsonhumanfertilityhavebeenconducted(seesection5.3).Inpreclinicalstudieswithdipyridamoleoracetylsalicylicacidnoimpairmentoffertilitywasobserved.Nostudiesontheeffectontheabilitytodriveandusemachineshavebeenperformed.However,patientsshouldbeadvisedthatsymptomssuchasdizzinessandconfusionalstatehavebeenreportedinclinicaltrials.Ifpatientsexperiencesuchsymptomstheyshouldavoidpotentiallyhazardoustaskssuchasdrivingoroperatingmachinery.Twolargescaletrials(ESPS-2,PRoFESS)enrollingatotalof26,934patients(thereof11,831patientswereallocatedtoASASANTIN)wereusedtodefinethesafetyprofileofASASANTIN.ThesedataaresupplementedwiththeextensiveThemostfrequentlyreportedadversereactionsareheadache,dizzinessandgastrointestinaleventssuchasdyspepsia,diarrhoea,nauseaandabdominalpain.MostimportantseriousadversereactionsassociatedwithASASANTINretardwereThefollowingadversereactionshavebeenreportedduringuseofASASANTINRetardinESPS-2andPRoFESSandfromcomplications Post-proceduralhaemorrhage, Notknown*nutritiondisorders Hypoglycaemia(children)2, Notknown*ThemostimportantseriousadversereactionsassociatedwithASASANTINRetardwerebleedingevents.DatafromESPS-2andPRoFESStrialsforbleedingeventsincludingmajorbleedingwereevaluated.Bleedingeventscategorizedasanybleeding,majorbleeding,intracranialbleedingandgastrointestinalbleeding:InthecontrolledESPS-2trial,1650patientsweretreatedintheASASANTINgroup(100%)and1649intheplacebogroup(100%).Themeandurationoftreatmentwas1.4years.Theoverallincidenceofbleedingwas8.7%intheASASANTINgroupand4.5%intheplacebogroup.Theincidenceofmajorbleedingwas1.6%and0.4%respectively.Theincidenceofintracranialbleedingwas0.6%and0.4%respectively,whilsttheincidenceofgastrointestinalbleedingInthePRoFESStrial,atotalof10,055patientsweretreatedintheASASANTINgroup(100%).Themeandurationoftreatmentwas1.9years.Theoverallincidenceofbleedingwas5.3%.Theincidenceofmajorbleedingwas3.3%.Theincidenceofintracranialbleedingwas1.2%(includingintraocularbleeding(0.2%)),whilsttheincidenceofgastrointestinalReportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinuedmonitoringofthebenefit/riskbalanceofthemedicinalproduct.HealthcareprofessionalsareaskedtoreportanysuspectedadversereactionsviaHPRAPharmacovigilance,EarlsfortTerrace,IRL–Dublin2;Tel:+35316764971;Fax:+35316762517.Website:www.hpra.ie;E-mail:medsafety@hpra.ie.Becauseofthedoseratioofdipyridamoletoacetylsalicylicacid,overdosageislikelytobedominatedbysignsandtissuedisorders Skinhaemorrhages(includingcontusion,1IdentifiedadversereactionsofDipyridamolemonotherapy2IdentifiedadversereactionsofAcetylsalicylicacidmonotherapy*TheseADRswerenotreportedinclinicaltrials,thereforeafrequencycouldnotbeFrequency:Verycommon>1in10;Common>1in100,<1in10;Uncommon>1inSymptomssuchasawarmfeeling,flushes,sweating,acceleratedpulse,restlessness,feelingofweakness,dizziness,andanginalcomplaintscanbeexpected.Adropinbloodpressureandtachycardiamightbeobserved.Salicylatepoisoningisusuallyassociatedwithplasmaconcentrations>350mg/L(2.5mmol/L).Mostadultdeathsoccurinpatientswhoseconcentrationsexceed700mg/L(5.1mmol/L).Singledoseslessthan100mg/kgareunlikelytocauseSymptomsofsalicylateoverdosecommonlyincludevomiting,dehydration,tinnitus,vertigo,deafness,sweating,warmextremitieswithboundingpulses,increasedrespiratoryrateandhyperventilation.Somedegreeofacid-basedisturbanceisAmixedrespiratoryalkalosisandmetabolicacidosiswithnormalorhigharterialpH(normalorreducedhydrogenionconcentration)isusualinadultsandchildrenovertheageoffouryears.Inchildrenagedfouryearsorless,adominantmetabolicacidosiswithlowarterialpH(raisedhydrogenionconcentration)iscommon.AcidosismayincreasesalicylateUncommonfeaturesofsalicylatepoisoningincludehaematemesis,hyperpyrexia,hypoglycaemia,hypokalaemia,thrombocytopenia,increasedINR/PTR,intravascularcoagulation,renalfailureandnon-cardiacpulmonaryoedema.Centralnervoussystemfeaturesincludingconfusion,disorientation,comaandconvulsionsarelesscommoninadultsthanDizzinessandtinnituscan,particularlyinelderlypatients,besymptomsofoverdose.Administrationofxanthinederivatives(e.g.aminophylline)mayreversethehaemodynamiceffectsofdipyridamoleoverdose.Duetoitswidedistributiontotissuesanditspredominantlyhepaticelimination,diypridamoleisnotlikelytobeaccessibletoenhancedremovalprocedures.Inthecaseofsalicylatepoisoningactivatedcharcoalshouldbegiventoadultswhopresentwithinonehourofingestionofmorethan250mg/kg.Theplasmasalicylateconcentrationshouldbemeasured,althoughtheseverityofpoisoningcannotbedeterminedfromthisaloneandtheclinicalandbiochemicalfeaturesmustbetakenintoaccount.Eliminationisincreasedbyurinaryalkalinisation,whichisachievedbytheadministrationof1.26%sodiumbicarbonate.TheurinepHshouldbemonitored.Correctmetabolicacidosiswithintravenous8.4%sodiumbicarbonate(firstcheckserumpotassium).Forceddiuresisshouldnotbeusedsinceitdoesnotenhancesalicylateexcretionandmaycausepulmonaryoedema.Haemodialysisisthetreatmentofchoiceforseverepoisoningandshouldbeconsideredinpatientswithplasmasalicylateconcentrations>700mg/L(5.1mmol/L),orlowerconcentrationsassociatedwithsevereclinicalormetabolicfeatures.Patientsundertenyearsorover70haveincreasedriskofsalicylatetoxicityandmayrequiredialysisatanearlierstage.TheantithromboticactionoftheAcetylsalicylicacid(aspirin)/dipyridamolecombinationisbasedonthedifferentbiochemicalmechanismsinvolved.Acetylsalicylicacid(aspirin)inactivatesirreversiblytheenzymecyclo-oxygenaseinplateletsthuspreventingtheproductionofthromboxaneA2,apowerfulinducerofplateletaggregationandDipyridamoleinhibitstheuptakeofadenosineintoerythrocytes,plateletsandendothelialcellsinvitroandinvivo;theinhibitionamountstoapproximately80%atmaximumandoccursdose-dependentlyattherapeuticconcentrations(0.5–2mcg/ml).Consequently,thereisanincreasedconcentrationofadenosinelocallytoactontheplateletA-receptor,stimulatingplateletadenylatecyclase,therebyincreasingplateletcAMPlevels.Thus,plateletaggregationinresponsetovariousstimulisuchasplateletactivatingfactor(PAF),collagenandadenosinediphosphate(ADP)isinhibited.Reducedplateletaggregationreducesplateletconsumptiontowardsnormallevels.Inaddition,adenosinehasavasodilatoreffectandthisisoneofthemechanismsbywhichdipyridamoleproducesDipyridamolehasalsobeenshowninstrokepatientstoreducethedensityofprothromboticsurfaceproteins(PAR-1:Thrombinreceptor)onplateletsaswellastoreducelevelsofc-reactiveprotein(CRP)andvonWillebrandFactor(vWF).In-vitroinvestigationshaveshownthatdipyridamoleselectivelyinhibitsinflammatorycytokines(MCP-1andMMP-9)arisingfromplatelet-monocyteinteraction.Dipyridamoleinhibitsphosphodiesterase(PDE)invarioustissues.WhilsttheinhibitionofcAMP-PDEisweak,therapeuticlevelsofdipyridamoleinhibitcGMP-PDE,therebyaugmentingtheincreaseincGMPproducedbyEDRF(endothelium-derivedrelaxingfactor,identifiedasnitricoxide(NO)).Dipyridamoleincreasesthereleaseoft-PAfrommicrovascularendothelialcellsandwasshowntoamplifytheantithromboticpropertiesofendothelialcellsonthrombusformationonadjacentsubendothelialmatrixinadosedependentmanner.Dipyridamoleisapotentradicalscavengerforoxy-andperoxy-radicals.Dipyridamolealsostimulatesthebiosynthesisandreleaseofprostacyclinbytheendotheliumandreducesthethrombogenicityofsubendothelialstructuresbyincreasingtheconcentrationoftheprotectivemediator13-HODE(13-Whereasacetylsalicylicacid(aspirin)inhibitsonlyplateletaggregation,dipyridamoleinadditioninhibitsplateletactivationandadhesion.Thereforeanadditionalbenefitfromcombiningbothdrugscanbeexpected.Experimentaldatasuggestthatibuprofenmayinhibittheeffectoflowdoseaspirinonplateletaggregationwhentheyaredosedconcomitantly.Inonestudy,whenasingledoseofibuprofen400mgwastakenwithin8hbeforeorwithin30minafterimmediatereleaseaspirindosing(8lmg),adecreasedeffectofASAontheformationofthromboxaneorplateletaggregationoccurred.However,thelimitationsofthesedataandtheuncertaintiesregardingextrapolationofexvivodatatotheclinicalsituationimplythatnofirmconclusionscanbemadeforregularibuprofenuse,andnoclinicallyrelevanteffectASASANTINRetard wasstudiedinadouble-blind,placebo-controlled,24-monthstudy(priortoentry.Patientswererandomizedtooneoffourtreatmentgroups:ASASANTINRetard(ASA/extended-releasedipyridamole)25mg/200mg;extended-releasedipyridamole(ER-DP)200mgalone;ASA25mgalone;orplacebo.Patientsreceivedonecapsuletwicedaily(morningandevening).Efficacyassessmentsincludedanalysesofstroke(fatalornonfatal)anddeath(fromallcauses)asconfirmedbyablindedmorbidityandmortalityassessmentgroup.InESPS-2ASASANTINRetardreducedtheriskofstrokeby23.1%comparedtoASA50mg/dayalone(p=0.006)andreducedtheriskofstrokeby24.7%comparedtoextended-releasedipyridamole400mg/dayalone(p=0.002).ASASANTINRetardreducedtheriskofstrokeby37%comparedtoplacebo(p<0.001).theextended-releasedipyridamoleformulation)andASA30-325mgdaily.Atotalof2739patientsafterischaemicstrokeofarterialoriginwereenrolledintheASA-alone(n=1376)andcombinationASAplusdipyridamole(n=1363)arm.Theprimaryoutcomeeventwasthecompositeofdeathfromallvascularcauses,non-fatalstroke,non-fatalmyocardialinfarction(MI),ormajorbleedingcomplications.PatientsintheASAplusdipyridamolegroupshoweda20%riskreduction(p<0.05)fortheprimarycompositeendpointcomparedwiththoseintheASAalonegroup(12.7%vs.15.7%;international,double-blind,double-dummy,activeandplacebocontrolled,2x2factorialstudytocompareASASANTINwithclopidogrel,andtelmisartanwithmatchingplacebointhepreventionofstrokeinpatientswhohadpreviouslyexperiencedanischaemicstrokeofnoncardioembolicorigin.Atotalof20,332patientswererandomizedtoASASANTIN(n=10,181)orclopidogrel(n=10,151),bothgivenonabackgroundofstandardtreatment.TheprimaryendpointwastheTheincidenceoftheprimaryendpointwassimilarinbothtreatmentgroups(9.0%forASASANTINvs.8.8%forclopidogrel;HR1.01,95%CI0.92-1.11).NosignificantdifferencebetweentheASASANTINandclopidogreltreatmentgroupsweredetectedforseveralotherimportantpre-specifiedendpoints,includingthecompositeofrecurrentstroke,thecompositeofrecurrentstrokeormajorhaemorrhagicevent(11.7%forASASANTINvs.11.4%forclopidogrel;HR1.03,95%CI0.95-1.11).Thefunctionalneurologicaloutcome3monthspostrecurrentstrokewasassessedbytheModifiedRankinScale(MRS)andnosignificantdifferenceinthedistributionoftheMRSbetweenASASANTINandclopidogrelwasobserved(p=0.3073byCochran-Armitagetestforlineartrend).Thereisnonoteworthypharmacokineticinteractionbetweentheextendedreleasepelletsofdipyridamoleandacetylsalicylicacid(aspirin).ThereforepharmacokineticsofASASANTINRetardisreflectedbythepharmacokineticsofWithdipyridamole,thereisdoselinearityforalldosesusedintherapy.Forlong-termtreatmentdipyridamolemodifiedreleasecapsules,formulatedaspelletsweredeveloped.ThepHdependentsolubilityofdipyridamolewhichpreventsdissolutioninthelowerpartsofthegastro-intestinaltract(wheresustainedreleasepreparationsmuststillreleasetheactiveprinciple)wasovercomebycombinationwithtartaricacid.Retardationisachievedbyadiffusionmembrane,whichissprayedontothepellets.Variouskineticstudiesatsteadystateshowed,thatallpharmacokineticparameterswhichareappropriatetocharacterisethepharmacokineticpropertiesofmodifiedreleasepreparationsareeitherequivalentorsomewhatimprovedwithdipyridamolemodifiedreleasecapsulesgivenb.i.d.comparedtodipyridamoletabletsadministeredt.d.s./q.d.s.