ARICEPT

Main information

  • Trade name:
  • ARICEPT Film Coated Tablet 10.0 Milligram
  • Dosage:
  • 10.0 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARICEPT Film Coated Tablet 10.0 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1447/010/002
  • Authorization date:
  • 04-07-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1447/010/002

CaseNo:2048059

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

G&ALicensingLtd

Ballymurray,Co.Roscommon,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Aricept10mgFilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom04/07/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ARICEPT10mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgdonepezilhydrochloride,equivalentto9.12mgdonepezilfreebase.

Alsocontainslactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromFrance:

Yellowround,biconvextabletsembossed‘ARICEPT’ononesideand‘10’ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ARICEPTTabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer'sdementia.

4.2Posologyandmethodofadministration

Adults/Elderly:

Treatmentisinitiatedat5mg/day(once-a-daydosing).ARICEPTshouldbetakenorally,intheevening,justpriorto

retiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinicalresponses

totreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobeachieved.

Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseofARICEPTcanbeincreasedto10

mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenot

beenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofARICEPTisseen.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Children:

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4.3Contraindications

ARICEPTiscontraindicatedinpatientswithaknownhypersensitivitytodonepezilhydrochloride,piperidine

derivatives,ortoanyexcipientsusedintheformulation.

4.4Specialwarningsandprecautionsforuse

TheuseofARICEPTinpatientswithsevereAlzheimer'sdementia,othertypesofdementiaorothertypesofmemory

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

Anaesthesia:ARICEPT,asacholinesteraseinhibitor,islikelytoexaggeratesuccinylcholine-typemusclerelaxation

duringanaesthesia.

CardiovascularConditions:Becauseoftheirpharmacologicalaction,cholinesteraseinhibitorsmayhavevagotonic

effectsonheartrate(e.g.,bradycardia).Thepotentialforthisactionmaybeparticularlyimportanttopatientswith"sick

sinussyndrome"orothersupraventricularcardiacconductionconditions,suchassinoatrialoratrioventricularblock.

Therehavebeenreportsofsyncopeandseizures.Ininvestigatingsuchpatientsthepossibilityofheartblockorlong

sinusalpausesshouldbeconsidered.

GastrointestinalConditions:Patientsatincreasedriskfordevelopingulcers,e.g.,thosewithahistoryofulcerdisease

orthosereceivingconcurrentnonsteroidalanti-inflammatorydrugs(NSAIDs),shouldbemonitoredforsymptoms.

However,theclinicalstudieswithARICEPTshowednoincrease,relativetoplacebo,intheincidenceofeitherpeptic

ulcerdiseaseorgastrointestinalbleeding.

Genitourinary:AlthoughnotobservedinclinicaltrialsofARICEPT,cholinomimeticsmaycausebladderoutflow

obstruction.

NeurologicalConditions:Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms.

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

TheadministrationofARICEPTconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsorantagonistsof

thecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

dementiaappearstobeduesolelytovascularcausesandtoexcludepatientswithAlzheimer'sdisease.Inthefirststudy,

themortalityrateswere2/198(1.0%)ondonepezilhydrochloride5mg,5/206(2.4%)ondonepezilhydrochloride10

mgand7/199(3.5%)onplacebo.Inthesecondstudy,themortalityrateswere4/208(1.9%)ondonepezil

hydrochloride5mg,3/215(1.4%)ondonepezilhydrochloride10mgand1/193(0.5%)onplacebo.Inthethirdstudy,

themortalityrateswere11/648(1.7%)ondonepezilhydrochloride5mgand0/326(0%)onplacebo.Themortalityrate

forthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumericallyhigherthaninthe

placebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityofdeathsinpatients

takingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelatedcauses,whichcouldbe

expectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallseriousnon-fatalandfatal

vasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegrouprelativetoplacebo.

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidine,ordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

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InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthatketoconazoleandquinidine,inhibitors

ofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.ThereforetheseandotherCYP3A4inhibitors,suchas

itraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecouldinhibitthemetabolismofdonepezil.

Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezilconcentrationsbyabout30%.Enzyme

inducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil.Sincethe

magnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinationsshouldbeusedwithcare.Donepezil

hydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalsothepotential

forsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,otherneuro-

muscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiacconduction.

4.6Pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

Ariceptshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation:

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

machines.

4.8Undesirableeffects

Themostcommonadverseeventsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.

Adversereactionsreportedasmorethananisolatedcasearelistedbelow,bysystemorganclassandbyfrequency.Frequencies

aredefinedas:verycommon>1/10)common>1/100,<1/10),uncommon>1/1,000,<1/100),rare>1/10,000,<1/1,000):veryrare

(<1/10000)andnotknown(cannotbeestimatedfromavailabledata)

SystemOrgan

Class VeryCommonCommon Uncommon Rare

Infectionsand

infestations Commoncold

Metabolismand

nutritiondisorders Anorexia

Psychiatricdisorders Hallucinations**

Agitation**

Aggressive

behaviour**

Nervoussystem

disorders Syncope*

Seizure* Extrapyramidal

symptoms Dizziness

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuationof

treatment.

***Incasesofunexplainedliverdysfunction,withdrawalofARICEPTshouldbeconsidered.

4.9Overdose

Theestimatedmedianlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreduced

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

salivation,miosis,fasciculationandlowerbodysurfacetemperature.

Overdosagewithcholinesteraseinhibitorscanresultincholinergiccrisischaracterizedbyseverenausea,vomiting,

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

Increasingmuscleweaknessisapossibilityandmayresultindeathifrespiratorymusclesareinvolved.

Asinanycaseofoverdose,generalsupportivemeasuresshouldbeutilised.Tertiaryanticholinergicssuchasatropine

maybeusedasanantidoteforARICEPToverdosage.Intravenousatropinesulphatetitratedtoeffectisrecommended:

aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesinblood

pressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwithquaternary

anticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/oritsmetabolitescanbe

Cardiacdisorders Bradycardia Sino-atrialblock

Atrioventricularblock

Gastrointestinal

disorders Diarrhoea Vomiting Gastrointestinal

haemorrhage

Nausea Abdominal

disturbance Gastricand

duodenalulcers

Hepato-biliary

disorders Liverdysfunction

includinghepatitis***

Skinand

subcutaneoustissue

disorders Rash

Pruritis

Musculoskeletal,

connectivetissue

andbonedisorders Musclecramps

Renalandurinary

disorders Urinaryincontinence

Generaldisorders

andadministration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Thepharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterase;ATC-codeN06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.

Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymethatispresentmainlyoutsidethecentralnervoussystem.

Alzheimer'sDementia

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofARICEPTproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocytemembranes)

of63.6%and77.3%,respectivelywhenmeasuredpostdose.Theinhibitionofacetylcholinesterase(AChE)inred

bloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesinADAS-cog,asensitivescalewhich

examinesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloridetoalterthecourseoftheunderlying

neuropathologyhasnotbeenstudied.ThusAriceptcannotbeconsideredtohaveanyeffectontheprogressofthe

disease.

EfficacyoftreatmentwithAricepthasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-yearduration.

Inthe6monthsclinicaltrials,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC+

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale

*p<0.05

**p<0.01

Ariceptproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowerejudged

treatmentresponders.

5.2Pharmacokineticproperties

Absorption:Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.Plasma

concentrationsandareaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeis

approximately70hours,thus,administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.

Approximatesteady-stateisachievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezil

hydrochlorideconcentrationsandtherelatedpharmacodynamicactivityshowlittlevariabilityoverthecourseofthe

day.

%Response

IntenttoTreatPopulation EvaluablePopulation

n=365 n=352

PlaceboGroup 10% 10%

Aricept5-mgGroup 18%* 18%*

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Distribution:Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaprotein

bindingoftheactivemetabolite6-O-desmethyldonepezilisnotknown.

Thedistributionofdonepezilhydrochlorideinvariousbodytissueshasnotbeendefinitivelystudied.However,ina

massbalancestudyconductedinhealthymalevolunteers,240hoursaftertheadministrationofasingle5mgdoseof

14C-labeleddonepezilhydrochloride,approximately28%ofthelabelremainedunrecovered.Thissuggeststhat

donepezilhydrochlorideand/oritsmetabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion:Donepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochrome

P450systemtomultiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mg

doseof14C-labeleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,

waspresentprimarilyasintactdonepezilhydrochloride(30%),6-O-desmethyldonepezil(11%-onlymetabolitethat

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

theglucuronideconjugateof5-O-desmethyldonepezil(3%).Approximately57%ofthetotaladministered

radioactivitywasrecoveredfromtheurine(17%asunchangeddonepezil),and14.5%wasrecoveredfromthefaeces,

suggestingbiotransformationandurinaryexcretionastheprimaryroutesofelimination.Thereisnoevidenceto

suggestenterohepaticrecirculationofdonepezilhydrochlorideand/oranyofitsmetabolites.

Plasmadonepezilconcentrationsdeclinewithahalflifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjectsorin

Alzheimer'sorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwiththoseofyoung

healthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteadystateconcentrations;meanAUCby

48%andmeanCmaxby39%(seesection4.2)

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seeSection4.9).Donepezilis

notmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffectswereobservedinvitroat

concentrationsovertlytoxictothecellsandmorethan3000timesthesteady-stateplasmaconcentrations.No

clastogenicorothergenotoxiceffectswereobservedinthemousemicronucleusmodelinvivo.Therewasnoevidence

ofoncogenicpotentialinlongtermcarcinogenicitystudiesineitherratsormice.

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstillbirthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seeSection

4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Microcrystallinecellulose

Hyprolose

Magnesiumstearate

Filmcoating

Talc

Macrogol

Hypromellose

Titaniumdioxide(E171)

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterpacksof28tabletscontainedinanoverlabelledoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialinstructions

7ParallelProductAuthorisationHolder

G&ALicensingLimited

Ballymurray

Co.Roscommon

Ireland

8ParallelProductAuthorisationNumber

PPA1447/10/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:July4th2008.

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