DONEPEZIL SYNTHON

Main information

  • Trade name:
  • DONEPEZIL SYNTHON
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DONEPEZIL SYNTHON
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0840/007/002
  • Authorization date:
  • 02-05-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0840/007/002

CaseNo:2076683

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

SynthonB.V.

Microweg22,6545CMNijmegen,Netherlands

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

DonepezilSynthon10mgfilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom22/04/2010until01/05/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 22/04/2010 CRN 2076683 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DonepezilSynthon10mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains10.44mgdonepezilhydrochloridemonohydrate,equivalentto10mgdonepezil

hydrochloride,equivalentto9.12mgofdonepezil.

Excipient:

Eachtabletcontains182mglactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Yellow,round,biconvex,film-coatedtablets,debossedwithD9EIononesideand10ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepezilhydrochlorideisindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer’s

dementia.

4.2Posologyandmethodofadministration

Adults/elderly

Treatmentisinitiatedat5mg/day(once-a-daydosing).Donepezilhydrochloridetabletsshouldbetakenorally,inthe

evening,justpriortoretiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowthe

earliestclinicalresponsestotreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezil

hydrochloridetobeachieved.Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseof

donepezilhydrochloridecanbeincreasedto10mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis

10mg.Dosesgreaterthan10mg/dayhavenotbeenstudiedinclinicaltrials.

Fordosesnotrealisable/practicablewiththisstrengthotherstrengthsofthismedicinalproductareavailable.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer’s

dementia.Diagnosisshouldbemadeaccordingtoacceptedguidelines(e.g.DSMIV,ICD10).Therapywithdonepezil

hydrochlorideshouldonlybestartedifacaregiverisavailablewhowillregularlymonitormedicinalproductintakefor

thepatient.Maintenancetreatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.

Therefore,theclinicalbenefitofdonepezilhydrochlorideshouldbereassessedonaregularbasis.Discontinuation

shouldbeconsideredwhenevidenceofatherapeuticeffectisnolongerpresent.Individualresponsetodonepezil

hydrochloridecannotbepredicted.

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Renalandhepaticimpairment

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents

Donepezilhydrochlorideisnotrecommendedforuseinchildrenandadolescents.

4.3Contraindications

Themedicinalproductiscontraindicatedinpatientswithhypersensitivitytodonepezilhydrochloride,piperidine

derivatives,ortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

TheuseofdonepezilhydrochlorideinpatientswithsevereAlzheimer’sdementia,othertypesofdementiaorother

typesofmemoryimpairment(e.g.,age-relatedcognitivedecline),hasnotbeeninvestigated.

Anaesthesia

Donepezilhydrochloride,asacholinesteraseinhibitor,islikelytoexaggeratesuccinylcholine-typemusclerelaxation

duringanaesthesia.

Cardiovascularconditions

Becauseoftheirpharmacologicalaction,cholinesteraseinhibitorsmayhavevagotoniceffectsonheartrate(e.g.

bradycardia).Thepotentialforthisactionmaybeparticularlyimportanttopatientswith"sicksinussyndrome"orother

supraventricularcardiacconductionconditions,suchassinoatrialoratrioventricularblock.

Therehavebeenreportsofsyncopeandseizures.Ininvestigatingsuchpatientsthepossibilityofheartblockorlong

sinusalpausesshouldbeconsidered.

Gastrointestinalconditions

Patientsatincreasedriskfordevelopingulcers,e.g.thosewithahistoryofulcerdiseaseorthosereceivingconcurrent

nonsteroidalanti-inflammatorydrugs(NSAIDs),shouldbemonitoredforsymptoms.However,theclinicalstudieswith

donepezilhydrochlorideshowednoincrease,relativetoplacebo,intheincidenceofeitherpepticulcerdiseaseor

gastrointestinalbleeding.

Genitourinary

Althoughnotobservedinclinicaltrialsofdonepezilhydrochloride,cholinomimeticsmaycausebladderoutflow

obstruction.

Neurologicalconditions

Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralisedconvulsions.However,seizure

activitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms.

Pulmonaryconditions

Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwithcaretopatientswitha

historyofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilhydrochlorideconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

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Severehepaticimpairment

Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

dementiaappearstobeduesolelytovascularcausesandtoexcludepatientswithAlzheimer’sdisease.Inthefirst

study,themortalityrateswere2/198(1.0%)ondonepezilhydrochloride5mg,5/206(2.4%)ondonepezil

hydrochloride10mgand7/199(3.5%)onplacebo.Inthesecondstudy,themortalityrateswere4/208(1.9%)on

donepezilhydrochloride5mg,3/215(1.4%)ondonepezilhydrochloride10mgand1/193(0.5%)onplacebo.Inthe

thirdstudy,themortalityrateswere11/648(1.7%)ondonepezilhydrochloride5mgand0/326(0%)onplacebo.The

mortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumericallyhigher

thanintheplacebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityofdeathsin

patientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelatedcauses,which

couldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallseriousnon-fataland

fatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegrouprelativeto

placebo.

InpooledAlzheimer’sdiseasestudies(n=4146),andwhentheseAlzheimer’sdiseasestudieswerepooledwithother

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezilhydrochloride.Medicinalproductinteractionstudiesperformedinvitroshowthat

ketoconazoleandquinidine,inhibitorsofCYP3A4and2D6respectively,inhibitdonepezilhydrochloridemetabolism.

Therefore,theseandotherCYP3A4inhibitors,suchasitraconazoleanderythromycin,andCYP2D6inhibitors,suchas

fluoxetine,couldinhibitthemetabolismofdonepezilhydrochloride.

Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezilhydrochlorideconcentrationsbyabout30%.

Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil

hydrochloride.Sincethemagnitudeofaninhibitingorinducingeffectisunknown,suchmedicinalproduct

combinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuro-muscularblockingagentsorcholinergicagonistsorbetablockingagentsthathaveeffectsoncardiacconduction.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilhydrochlorideinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3).The

potentialriskforhumansisunknown.

Donepezilhydrochlorideshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilhydrochlorideisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedin

humanbreastmilkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilhydrochlorideshould

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4.7Effectsonabilitytodriveandusemachines

Donepezilhydrochloridehasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilhydrochloridecaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthe

dose.Thetreatingphysicianshouldroutinelyevaluatetheabilityofpatientsondonepezilhydrochloridetocontinue

drivingoroperatingcomplexmachines.

4.8Undesirableeffects

Themostcommonadverseeventsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.

Adversereactionsreportedasmorethananisolatedcasearelistedbelow,bysystemorganclassandbyfrequency.

Frequenciesaredefinedas:verycommon(>1/10)common(>1/100,<1/10),uncommon(>1/1,000,<1/100),rare(>

1/10,000,<1/1,000),veryrare(<1/10,000)andnotknown(cannotbeestimatedfromavailabledata).

VeryCommon Common Uncommon Rare

SystemOrgan

Class

Investigations -Minorincrease

inserum

concentrationof

musclecreatine

kinase

Cardiacdisorders -Bradycardia -Sino-atrialblock

-Atrioventricu-lar

block

Nervoussystem

disorders -Syncope*

-Dizziness

-Insomnia -Seizure* -Extrapyramidal

symptoms

Gastrointestinal

disorders -Diarrhoea

-Nausea -Vomiting

-Abdominal

disturbance -Gastrointestin-al

haemorrhage

-Gastricand

duodenalulcers

Renalandurinary

disorders -Urinary

incontinence

Skinand

subcutaneous

tissuedisorders -Rash

-Pruritis

Musculoskeletal

andconnective

tissuedisorders -Musclecramps

Metabolismand

nutrition

disorders -Anorexia

Infectionsand

infestations -Commoncold

Injury,poisoning

andprocedural

complications -Accident

Generaldisorders

administration -Headache -Fatigue

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Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4).

Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionor

discontinuationoftreatment.

Incasesofunexplainedliverdysfunction,withdrawalofdonepezilhydrochlorideshouldbeconsidered.

4.9Overdose

Theestimatedmedianlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreduced

spontaneousmovement,proneposition,staggeringgait,lacrimation,clonicconvulsions,depressedrespiration,

salivation,miosis,fasciculationandlowerbodysurfacetemperature.

Overdosewithcholinesteraseinhibitorscanresultincholinergiccrisischaracterizedbyseverenausea,vomiting,

salivation,sweating,bradycardia,hypotension,respiratorydepression,collapseandconvulsions.Increasingmuscle

weaknessisapossibilityandmayresultindeathifrespiratorymusclesareinvolved.

Asinanycaseofoverdose,generalsupportivemeasuresshouldbeutilised.Tertiaryanticholinergicssuchasatropine

maybeusedasanantidotefordonepezilhydrochlorideoverdose.Intravenousatropinesulphatetitratedtoeffectis

recommended:aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypical

responsesinbloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwith

quaternaryanticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/orits

metabolitescanberemovedbydialysis(haemodialysis,peritonealdialysis,orhaemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterases

ATC-codeN06DA02

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymethatispresentmainlyoutsidethecentralnervoussystem.

Alzheimer’sDementia

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilhydrochlorideproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredin

erythrocytemembranes)of63.6%and77.3%,respectivelywhenmeasuredpostdose.Theinhibitionof

acetylcholinesterase(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesin

ADAS-cog,asensitivescalethatexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochlorideto

alterthecourseoftheunderlyingneuropathologyhasnotbeenstudied.Thus,donepezilhydrochloridecannotbe

siteconditions

Hepatobiliary

disorders -Liverdysfunction

including

hepatitis***

Psychiatric

disorders -Hallucinations

-Agitation**

-Aggressive

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Efficacyoftreatmentwithdonepezilhydrochloridehasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-

monthdurationand2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepezilhydrochloridetreatmentusinga

combinationofthreeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterview

BasedImpressionofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLiving

SubscaleoftheClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesand

personalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response= ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC+

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale

p<0.05

p<0.01

Donepezilhydrochlorideproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswho

werejudgedtreatmentresponders.

5.2Pharmacokineticproperties

Absorption

Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.Plasmaconcentrationsand

areaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeisapproximately70hours,thus,

administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.Approximatesteady-stateis

achievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezilhydrochloride

concentrationsandtherelatedpharmacodynamicactivityshowlittlevariabilityoverthecourseoftheday.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution

Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaproteinbindingofthe

activemetabolite6-O-desmethyldonepezilisnotknown.Thedistributionofdonepezilhydrochlorideinvariousbody

tissueshasnotbeendefinitivelystudied.However,inamassbalancestudyconductedinhealthymalevolunteers,240

hoursaftertheadministrationofasingle5mgdoseof14C-labelleddonepezilhydrochloride,approximately28%of

thelabelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/oritsmetabolitesmaypersistinthe

bodyformorethan10days.

Metabolism/Excretion

DonepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochromeP450systemto

multiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mgdoseof

14C-labelleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,was

presentprimarilyasintactdonepezilhydrochloride(30%),6-O-desmethyldonepezil(11%–onlymetabolitethat

exhibitsactivitysimilartodonepezilhydrochloride),donepezil-cis-N-oxide(9%),5-O-desmethyldonepezil(7%)and

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Donepezilhydrochloride5

mgtabletsGroup 18%* 18%*

Donepezilhydrochloride

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Approximately57%ofthetotaladministeredradioactivitywasrecoveredfromtheurine(17%asunchangeddonepezil

hydrochloride),and14.5%wasrecoveredfromthefaeces,suggestingbiotransformationandurinaryexcretionasthe

primaryroutesofelimination.Thereisnoevidencetosuggestenterohepaticrecirculationofdonepezilhydrochloride

and/oranyofitsmetabolites.

Plasmadonepezilhydrochlorideconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhydrochloridehasnotbeenformallystudiedinhealthyelderly

subjects,orinAlzheimer’sorvasculardementiapatients.However,meanplasmalevelsinpatientscloselyagreedwith

thoseofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilhydrochloridesteadystateconcentrations;

meanAUCby48%andmeanCmaxby39%(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seesection4.9).

Donepezilhydrochlorideisnotmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffects

wereobservedinvitroatconcentrationsovertlytoxictothecellsandmorethan3000timesthesteady-stateplasma

concentrations.Noclastogenicorothergenotoxiceffectswereobservedinthemousemicronucleusmodelinvivo.

Therewasnoevidenceofoncogenicpotentialinlongtermcarcinogenicitystudiesineitherratsormice.

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstillbirthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seesection

4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

Microcrystallinecellulose(E460)

Sodiumstarchglycolate(typeA)

Hydroxypropylcellulose(E463)

Magnesiumstearate(E572)

Film-coating

Hypromellose(E464)

Lactosemonohydrate

Macrogol4000

Titaniumdioxide(E171)

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

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6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Cardboardboxescontainingblisters(PVC/Aluminium)with7,28,30,50,56,60,84,98,100or120tabletsand

hospitalblisters(unitdoseblister)(PVC/Aluminium)with50tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

SynthonBV

Microweg22

6545CMNijmegen

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA840/007/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2ndMay2008

10DATEOFREVISIONOFTHETEXT

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