ARICEPT 5 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
DONEPEZIL HYDROCHLORIDE
Available from:
Imbat Limited
ATC code:
N06DA02
INN (International Name):
DONEPEZIL HYDROCHLORIDE
Dosage:
5 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Anticholinesterases
Authorization status:
Authorised
Authorization number:
PPA1151/037/001
Authorization date:
2008-01-11

PACKAGELEAFLET:INFORMATIONFORTHEUSER

Aricept ® 5mgFilm-coated Tablets

(donepezilhydrochloride)

Youand yourcaregivershould read allofthis

leafletcarefullybeforeyoustarttaking this

medicine.

Keepthisleaflet.Youmayneedtoreaditagain.

Ifyou haveanyfurtherquestions,askyourdoctoror

pharmacist.

Thismedicinehasbeenprescribedforyou.Donotpassiton

toothers.Itmayharmthem,eveniftheirsymptomsarethe

sameasyours.

Ifanyofthesideeffectsgetserious,orifyounoticeany

sideeffectsnotlistedinthisleaflet,pleasetellyourdoctor

orpharmacist.

Inthisleaflet:

1.What Ariceptisandwhatitisusedfor

2.BeforeyoutakeAricept

3.HowtotakeAricept

4.Possiblesideeffects

5.HowtostoreAricept

6.Furtherinformation

1.WhatAriceptis and whatitis used for

Aricept(donepezilhydrochloride)belongsto agroupofmedicines

calledacetylcholinesteraseinhibitors.

Donepezilincreasesthelevelsofasubstance(acetylcholine)in

thebraininvolvedinmemoryfunctionbyslowingdownthebreak

downofacetylcholine.

Itisusedtotreat thesymptomsofdementiainpeoplediagnosed

ashavingmildandmoderatelysevereAlzheimer'sdisease.The

symptomsincludeincreasingmemoryloss,confusionand

behaviouralchanges.Asaresult,sufferersofAlzheimer'sdisease

finditmoreandmoredifficulttocarryouttheirnormaldaily

activities.

Ariceptisforuseinadultpatientsonly.

2.Before youtake Aricept

DoNOTtakeAricept

ifyouareallergic(hypersensitive)todonepezil

hydrochloride,ortopiperidinederivatives,oranyofthe

otheringredientsofAriceptlistedinsection6

TakespecialcarewithAricept

TellyourdoctororpharmacistbeforestartingtotakeAriceptif

you haveorhavehad:

stomachorduodenalulcers

seizures(fits)orconvulsions

aheartcondition(irregularorveryslowheartbeat)

asthmaorotherlongtermlungdisease

liverproblemsorhepatitis

difficultypassingurineormildkidneydisease

Alsotellyourdoctorifyouarepregnantorthinkyoumightbe

pregnant.

Takingothermedicines

Pleasetellyourdoctororpharmacistifyouaretaking,orhave

recentlytaken,anyothermedicine.Thisincludesmedicinesthat

yourdoctorhasnotprescribedforyoubutwhichyou havebought

yourselffromachemist/pharmacist.Italso appliestomedicines

youmaytakesometimeinthefutureifyoucontinuetotake

Aricept.Thisisbecausethesemedicinesmayweakenor

strengthentheeffectsofAricept.

Especiallytellyourdoctorifyouaretakinganyofthefollowing

typesofmedicines:

otherAlzheimer'sdiseasemedicinese.g.galantamine

painkillersortreatmentforarthritise.g.aspirin,non-

steroidalanti-inflammatory(NSAID)drugssuchas

ibuprofen,ordiclofenacsodium

anticholinergicsmedicinese.g.tolterodine

antibioticse.g.erythromycin,rifampicin

anti-fungalmedicinee.g.ketoconazole

anti-depressantse.g.fluoxetine

anticonvulsantse.g.phenytoin,carbamazepine

medicationforaheartconditione.g. quinidine, beta-

blockers(propanololandatenolol)

musclerelaxantse.g.diazepam,succinylcholine

generalanaesthetic

medicinesobtainedwithoutaprescriptione.g.herbal

remedies

Ifyouaregoingtohaveanoperationthatrequiresyoutohavea

generalanaesthetic,youshouldtellyourdoctorandthe

anaesthetistthatyouaretakingAricept.Thisisbecauseyour

medicinemayaffecttheamountofanaestheticneeded.

Ariceptcanbeusedinpatientswithkidneydiseaseormildto

moderateliverdisease.Tellyourdoctorfirstifyouhavekidneyor

liverdisease.Patientswithsevereliverdiseaseshouldnottake

Aricept.

Tellyourdoctororpharmacistthenameofyourcaregiver.Your

caregiverwillhelpyoutotakeyourmedicineasitisprescribed.

TakingAriceptwithfoodanddrink

FoodwillnotinfluencetheeffectofAricept.

Ariceptshould notbetakenwithalcoholbecausealcoholmay

changeitseffect.

Pregnancyandbreast-feeding

Ariceptshouldnotbeusedwhilebreast-feeding.

Ifyou arepregnant,orthinkyoumightbepregnant,askyour

doctorforadvicebeforetakinganymedicine.

Drivingandusingmachines

Alzheimer'sdiseasemayimpairyourabilitytodriveoroperate

machineryandyoumustnotperformtheseactivities unlessyour

doctortellsyouthatitissafetodoso.

Also,yourmedicinecan causetiredness,dizzinessandmuscle

cramp.Ifyouexperienceanyoftheseeffectsyoumustnotdrive

or operatemachinery.

Importantinformationaboutsomeofthe

ingredientsofAricept

Thismedicinecontainslactose.Ifyouhavebeentoldbyyour

doctorthatyouhaveintolerancetosomesugars,youshould

contactyourdoctorbeforetakingAricept.

3.How totakeAricept

HowmuchAriceptshouldyoutake?

Usually,youwillstartbytaking5mg(onewhitetablet)every

night.Afteronemonth,yourdoctormaytellyoutotake10mg

(oneyellowtablet) every night.

SwallowyourAricepttabletwithadrinkofwaterbeforeyougoto

bed atnight.

Thetablet strengthyouwilltakemaychangedependingonthe

lengthoftimeyou havebeen takingthemedicineandonwhat

yourdoctorrecommends.Themaximum recommendeddoseis

10mgeachnight.

Alwaysfollowyourdoctor's,orpharmacist'sadviceabouthowand

when totakeyourmedicine.

Donotalterthedoseyourselfwithoutyourdoctor'sadvice.

ForhowlongshouldyoutakeAricept?

Yourdoctororpharmacistwilladviseyouonhowlongyoushould

continuetotakeyourtablets.Youwillneedtoseeyourdoctor

fromtimetotimetoreviewyourtreatment andassessyour

symptoms.

IfyoustoptakingAricept

Donotstoptakingthetabletsunlesstoldtodosobyyourdoctor.

IfyoustoptakingAricept,thebenefitsofyourtreatmentwill

graduallyfadeaway.

IfyoutakemoreAriceptthanyoushould

DONOT takemorethan onetableteach day.Callyourdoctor

immediatelyifyoutakemorethanyoushould.Ifyoucannot

contactyourdoctor,contactthelocalhospitalAccidentand

Emergencydepartmentatonce.Alwaystakethetabletsandthe

cartonwithyoutothehospitalsothatthedoctorknowswhat has

beentaken.

Symptomsofoverdosingincludefeeling and beingsick,drooling,

sweating,slowheartrate,lowbloodpressure(light-headedness

ordizzinesswhenstanding),breathingproblems,losing

consciousness andseizures(fits)orconvulsions.

IfyouforgettotakeAricept

Ifyouforget totakeatablet,justtakeonetablet thefollowing

dayattheusualtime.Donottakeadoubledosetomakeupfora

forgottentablet.Ifyouforgettotakeyourmedicineformorethan

oneweek,callyourdoctorbeforetakinganymoremedicine.

4.Possible side effects

Likeallmedicines,Ariceptcancausesideeffects,althoughnot

everybodygetsthem.

Thefollowingsideeffectshavebeenreportedbypeopletaking

Aricept.

Tell your doctor ifyouhaveanyoftheseeffectswhileyou

aretakingAricept.

Seriousside effects:

Youmusttellyourdoctorimmediatelyifyounoticetheseserious

sideeffectsmentioned.Youmayneedurgentmedicaltreatment.

liverdamagee.g.hepatitis.Thesymptomsofhepatitisare

feelingorbeingsick,lossofappetite,feelinggenerally

unwell,fever,itching,yellowingoftheskin andeyes,and

darkcolouredurine(affects1to 10usersin10,000)

stomachorduodenalulcers.Thesymptomsofulcersare

stomachpainanddiscomfort(indigestion)feltbetweenthe

navelandthebreastbone(affects1to10usersin1,000)

bleedingin thestomach orintestines.Thismaycauseyouto

passblacktarlikestoolsorvisiblebloodfromtherectum

(affects1 to10usersin1,000)

seizures(fits)orconvulsions(affects 1to10usersin1,000)

feverwithmusclestiffness,sweatingoraloweredlevelof

consciousness(adisordercalled“NeurolepticMalignant

Syndrome”)(affectslessthan1userin10,000)

Verycommonsideeffects(affectsmorethan1userin10):

diarrhoea

feelingorbeingsick

headaches

Commonsideeffects(affects1 to10 usersin100):

musclecramp

tiredness

difficultyinsleeping(insomnia)

thecommoncold

lossofappetite

hallucinations(seeingorhearingthingsthatarenotreally

there)

unusualdreamsincludingnightmares

agitation

aggressivebehaviour

fainting

dizziness

stomachfeelinguncomfortable

rash

itching

passingurineuncontrollably

pain

accidents(patientsmaybemorepronetofallsand

accidentalinjury)

Uncommonsideeffects(affects 1to 10usersin1,000):

slowheartbeat

Raresideeffects(affects1to10 usersin10,000):

stiffness,shakingoruncontrollablemovementespeciallyof

thefaceandtonguebutalsoofthelimbs

Ifanyofthe side effectsgetsserious,or ifyounoticeany

side effectsnotlistedinthis leaflet,pleasetell your doctor

or pharmacist.

5.How tostoreAricept

Donotstorethismedicineabove30°C.

Keepoutofthesight andreachofchildren.

DONOT useAricepttabletsaftertheexpirydatethatisprintedon

thelabel.Theexpirydatereferstothelastdayofthatmonth.

Ifyourdoctortellsyoutostoptakingyourmedicine,youshould

return anyyou havenotusedtoyourpharmacistforsafe

disposal.

Ifyourtabletsappeartobediscoloured, damaged,orshowany

othersignsofdeterioration,pleasereturntoyourpharmacistwho

willadviseyou.

Thismedicineisforyou.Donotshareitwithanyoneelseevenif

theyhavethesamesymptomsasyou.

Medicinesshouldnotbedisposedofviawastewaterorhousehold

waste.Askyourpharmacisthowtodisposeofmedicinesnolonger

required.Thesemeasureswillhelptoprotecttheenvironment.

6.Furtherinformation

WhatdoesAriceptcontain?

Theactivesubstanceisdonepezilhydrochloride.Eachtablet

contains5mgofdonepezilhydrochloride.

Theotheringredientsare:lactosemonohydrate,

maizestarch,microcrystallinecellulose,hyprolose,

magnesiumstearate,talc,macrogol,hypromelloseand

titaniumdioxide(E171).

WhatdoesAriceptlooklike?

Ariceptarewhite, round,biconvexfilm-coatedtablets

marked'ARICEPT'ononesideand'5'on theother.

WhatisinapackofAricept?

Yourmedicineissuppliedinblisterpacksof28tablets.

Manufacturer

Yourtabletsaremanufacturedby:EisaiManufacturingLtd.,

MosquitoWay, Hatfield, Herts., AL109SN,UK.

ProcuredfromwithintheEUbytheParallelProduct Authorisation

holder:ImbatLtd,UnitL2,NorthRingBusinessPark,Santry,

Dublin9.

Theproductisrepackagedby:

DoncasterPharmaceuticalsGroupLtd,KirkSandall,Doncaster,

SouthYorkshire,DN31QR,UK.

Distributed by:EurodrugLtd,Santry, Dublin9.

PPANo:1151/37/1

Leafletrevision&issuedate(ref):22.10.13

Aricept®isaregisteredtrademarkofEisaiR&D Management

Co.,Ltd

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aricept5mgfilmcoatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgdonepezilhydrochloride.

Excipients:lactosemonohydrate

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromItaly:

White,round,biconvextabletswithnomarkings.

ProductimportedfromCzechRepublic,PolandandtheUnitedKingdom:

White,round,biconvexfilm-coatedtablesmarked'Aricept'ononesideand'5'ontheother

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,agonistsorantagonistsofthe

cholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

NeurolepticMalignantSyndrome(NMS):NMS,apotentiallylife-threateningconditioncharacterisedbyhyperthermia,

musclerigidity,autonomicinstability,alteredconsciousnessandelevatedserumcreatinephosphokinaselevels,has

beenreportedtooccurveryrarelyinassociationwithdonepezil,particularlyinpatientsalsoreceivingconcomitant

antipsychotics.Additionalsignsmayincludemyoglobinuria(rhabdomyolysis)andacuterenalfailure.Ifapatient

developssignsandsymptomsindicativeofNMS,orpresentswithunexplainedhighfeverwithoutadditionalclinical

manifestationsofNMS,treatmentshouldbediscontinued.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

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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.

Themajorityofdeathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvarious

vascularrelatedcauses,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.An

analysisofallseriousnon-fatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthe

donepezilhydrochloridegrouprelativetoplacebo.

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdoesnotinhibitthemetabolismoftheophylline,warfarin,

cimetidine,ordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andto

aminorextent2D6areinvolvedinthemetabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthat

ketoconazoleandquinidine,inhibitorsofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.Thereforethese

andotherCYP3A4inhibitors,suchasitraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecould

inhibitthemetabolismofdonepezil.Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezil

concentrationsbyabout30%.Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreduce

thelevelsofdonepezil.Sincethemagnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinations

shouldbeusedwithcare.Donepezilhydrochloridehasthepotentialtointerferewithmedicationshaving

anticholinergicactivity.

Thereisalsothepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchas

succinylcholine,otherneuro-muscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhave

effectsoncardiacconduction.

4.6Fertility,pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

Ariceptshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation:

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

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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)

SystemOrgan

Class Very

Common Common Uncommon Rare VeryRare

Infectionsand

infestations Commoncold

Metabolismand

nutrition

disorders Anorexia

Psychiatric

disorders Hallucinations**

Agitation**

Aggressive

behaviour**

Abnormaldreams

andNightmares**

Nervoussystem

disorders Syncope*

Dizziness

Insomnia Seizure* Extrapyramidal

symptoms Neuroleptic

Malignant

Syndrome

Cardiacdisorders Bradycardia Sino-atrial

block

Atrioventricular

block

Gastrointestinal

disorders Diarrhoea

Nausea Vomiting

Abdominal

disturbance Gastrointestinal

haemorrhage

Gastricand

duodenalulcers

Hepato-biliary

disorders Liver

dysfunction

including

hepatitis***

Skinand

subcutaneous

tissuedisorders Rash

Pruritis

Musculoskeletal,

connectivetissue

andbone

disorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

Generaldisorders

administration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,abnormaldreams,nightmares,agitationandaggressivebehaviourhaveresolvedondose-

reductionordiscontinuationoftreatment.

***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.Increasingmuscle

weaknessisapossibilityandmayresultindeathifrespiratorymusclesareinvolved.

Asinanycaseofoverdose,generalsupportivemeasuresshouldbeutilised.Tertiaryanticholinergicssuchasatropine

maybeusedasanantidoteforARICEPToverdosage.Intravenousatropinesulphatetitratedtoeffectisrecommended:

aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesinblood

pressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwithquaternary

anticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/oritsmetabolitescanbe

removedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

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.

ThusAriceptcannotbeconsideredtohaveanyeffectontheprogressofthedisease.

EfficacyoftreatmentwithAricepthasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-yearduration.

Inthe6monthsclinicaltrials,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC

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poisoning Accident Irish Medicines Board

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*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,plasmadonepezilhydrochlorideconcentrationsandtherelatedpharmacodynamicactivityshow

littlevariabilityoverthecourseoftheday.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution:Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaprotein

bindingoftheactivemetabolite6-O-desmethyldonepezilisnotknown.Thedistributionofdonepezilhydrochloridein

variousbodytissueshasnotbeendefinitivelystudied.However,inamassbalancestudyconductedinhealthymale

volunteers,240hoursaftertheadministrationofasingle5mgdoseof14C-labeleddonepezilhydrochloride,

approximately28%ofthelabelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/orits

metabolitesmaypersistinthebodyformorethan10days.

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

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Aricept5-mgGroup 18%* 18%*

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/12/2013 CRN 2141113 page number: 6

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)

6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelflifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Italy:

Blisterstripsinacardboardcarton

Packsize:28tablets

CzechRepublic,Poland&UK:

Overlabelledcardboardoutercontainingblisterstrips

Packsize:28tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/12/2013 CRN 2141113 page number: 7

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLimited

UnitL2

NorthRingBusinessPark

Santry

Dublin9

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1151/037/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:11thJanuary2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/12/2013 CRN 2141113 page number: 8

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