DONEPEZIL HYDROCHORIDE

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1327/011/002
  • Authorization date:
  • 20-02-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1327/011/002

CaseNo:2043229

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

OrionCorporation

Orionintie1,FIN-02200Espoo,Finland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Donepezilhydrochoride10mgFilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/02/2009until19/02/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 23/02/2009 CRN 2043229 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Donepezilhydrochloride10mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Donepezilhydrochloride10mg,film-coatedtablet:

Eachfilm-coatedtabletcontains10mgofdonepezilhydrochloride,equivalentto9.12mgofdonepezil.

Excipient:approx.150.71mgoflactose/film-coatedtablet

3PHARMACEUTICALFORM

Film-coatedtablet.

White,roundtabletswithadiameterof9.3mmapproximatelybearingabreaklineononeside.

Thetabletcanbedividedintoequalhalves.

Forfulllistofexcipients,seesection6.1

4CLINICALPARTICULARS

4.1TherapeuticIndications

Donepezilhydrochloride film-coatedtabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevere

Alzheimer'sdementia.

4.2Posologyandmethodofadministration

Adults/Elderly

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

justpriortoretiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliest

clinicalresponsestotreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobe

achieved.Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseofdonepezilhydrochloridecan

beincreasedto10mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan

10mg/dayhavenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofdonepezilhydrochlorideisseen.

Renalandhepaticimpairment

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

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Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Children

Donepezilhydrochlorideisnotrecommendedforuseinchildren

4.3Contraindications

Hypersensitivitytotheactivesubstance,piperidinederivatives,ortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

TheuseofdonepezilinpatientswithsevereAlzheimer'sdementia,othertypesofdementiaorothertypesofmemory

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

Anaesthesia:Donepezilhydrochloride,asacholinesteraseinhibitor,islikelytoexaggeratesuccinylcholine-typemuscle

relaxationduringanaesthesia.

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,theclinicalstudieswithdonepezilshowednoincrease,relativetoplacebo,intheincidenceofeitherpeptic

ulcerdiseaseorgastrointestinalbleeding.

Genitourinary:Althoughnotobservedinclinicaltrialsofdonepezil,cholinomimeticsmaycausebladderoutflow

obstruction.

NeurologicalConditions:Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms.

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilhydrochlorideconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

antagonistsofthecholinergicsystemshouldbeavoided.

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

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Inthesecondstudy,themortalityrateswere4/208(1.9%)ondonepezilhydrochloride5mg,3/215(1.4%)ondonepezil

hydrochloride10mgand1/193(0.5%)onplacebo.Inthethirdstudy,themortalityrateswere11/648(1.7%)on

donepezilhydrochloride5mgand0/326(0%)onplacebo.

ThemortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumerically

higherthanintheplacebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityof

deathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelated

causes,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallserious

non-fatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegroup

relativetoplacebo.

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andto

aminorextent2D6areinvolvedinthemetabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthat

ketoconazoleandquinidine,inhibitorsofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.Therefore

theseandotherCYP3A4inhibitors,suchasitraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetine

couldinhibitthemetabolismofdonepezil.Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezil

concentrationsbyabout30%.Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreduce

thelevelsofdonepezil.Sincethemagnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinations

shouldbeusedwithcare.Donepezilhydrochloridehasthepotentialtointerferewithmedicationshaving

anticholinergicactivity.Thereisalsothepotentialforsynergisticactivitywithconcomitanttreatmentinvolving

medicationssuchassuccinylcholine,otherneuro-muscularblockingagentsorcholinergicagonistsorbetablocking

agentswhichhaveeffectsoncardiacconduction.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

Donepezilhydrochlorideshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

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4.8Undesirableeffects

Adversereactionsreportedasmorethananisolatedcasearelistedbelow,bysystemorganclassandbyfrequency

*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuationof

treatment.

SystemOrganClass Very

Common

(1/10) Common(1/100to

<1/10) Uncommon(1/1,000

to<1/100) Rare(1/10,000to

<1/1,000)

Infectionsand

infestations CommonCold

Metabolismand

nutritiondisorders Anorexia

Psychiatricdisorders Hallucinations**

Agitation**

Aggressivebehaviour

NervousSystem

disorders Syncope*

Dizziness

Insomnia

fainting Seizure* Extrapyramidal

symptoms

Cardiacdisorders Bradycardia Sino-atrialblock

Atrioventricular

block

Gastrointestinal

disorders Diarrhoea

Nausea VomitingAbdominal

disturbance Gastrointestinal

haemorrhage

Gastricandduodenal

ulcers

Hepato-biliary

disorders Liverdysfunction

including

hepatitis***

SkinandSubcutaneous

tissuedisorders Rash

Puritis

Musculoskeletal

connectivetissueand

bonedisorders Musclecramps

Renalandurinary

disorders Urinaryincontinence

GeneralDisordersand

administrationsite

conditions Headache Fatigue

Pain

Investigations Minorincreasein

serumconcentrationof

musclecreatinekinase

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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

maybeusedasanantidotefordonepezilhydrochlorideoverdosage.Intravenousatropinesulphatetitratedtoeffectis

recommended:aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypical

responsesinbloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwith

quaternaryanticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/orits

metabolitescanberemovedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterase.

ATC-code:N06DA02

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,asensitivescalewhichexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloride

toalterthecourseoftheunderlyingneuropathologyhasnotbeenstudied.Thusdonepezilhydrochloridecannotbe

consideredtohaveanyeffectontheprogressofthedisease.

Efficacyoftreatmentwithdonepezilhydrochloridehasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-

monthdurationand2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

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NodeteriorationofCIBIC+

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale

*p<0.05

**p<0.01

Donepezilproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowerejudged

treatmentresponders.

5.2Pharmacokineticproperties

Absorption:Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.Plasma

concentrationsandareaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeis

approximately70hours,thus,administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.

Approximatesteady-stateisachievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezil

hydrochlorideconcentrationsandtherelatedpharmacodynamicactivityshowlittlevariabilityoverthecourseofthe

day.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution:Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaprotein

bindingoftheactivemetabolite6-O-desmethyldonepezilinnotknown.Thedistributionofdonepezilhydrochloridein

variousbodytissueshasnotbeendefinitivelystudied.

However,inamassbalancestudyconductedinhealthymalevolunteers,240hoursaftertheadministrationofasingle

5mgdoseof 14

C-labelleddonepezilhydrochloride,approximately28%ofthelabelremainedunrecovered.This

suggeststhatdonepezilhydrochlorideand/oritsmetabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion:Donepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochrome

P450systemtomultiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mg

doseof 14

C-labelleddonepezilhydrochloride,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.

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Donepezil5-mgGroup 18%* 18%*

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Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjectsorin

Alzheimer'sorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwiththoseofyoung

healthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteadystateconcentrations;meanAUCby

48%andmeanC

by39%(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

Tabletcore:

LactoseMonohydrate

Maizestarch

Hydroxypropylcellulose

Cellulose,Microcrystalline

MagnesiumStearate

Film-coating:

OpadryWhite:

Hypromellose2910(E464),

Titaniumdioxide(E171),

PropyleneGlycol,

Talc

6.2Incompatibilities

Notapplicable

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Donotstoreabove30 ˚C.

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6.5Natureandcontentsofcontainer

Tabletsareprovidedinblisterpacks(PVC-PE-PVDC/Aluminiumblisters)

14,28,56,84,98and112tablets(inBlistersof14)

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

OrionCorporation

Orionintine1

FIN–02200Espoo

Finland

8MARKETINGAUTHORISATIONNUMBER

PA1327/11/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20 th

February2009

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