DONEPEZIL HYDROCHLORIDE

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1470/001/002
  • Authorization date:
  • 17-04-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Donepezilhydrochloride10mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each10mgfilm-coatedtabletcontains10mgdonepezilhydrochloride(asmonohydrate),equivalentto9.12mgof

donepezil.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

Whiteoralmostwhite,odourlessoralmostodourless,round,biconvexfilm-coatedtabletswithstylizedE382onone

side.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepezilhydrochlorideisindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer’s

dementia.

4.2Posologyandmethodofadministration

Adults/Elderly

Treatmentisinitiatedat5mgdonepezilhydrochlorideonceaday.Itshouldbetakenorallyintheevening,justpriorto

retiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinicalresponses

totreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepeziltobeachieved.Followingaone-

monthclinicalassessmentoftreatmentat5mg/day,thedoseofdonepezilhydrochloridecanbeincreasedto10mg

onceaday.Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenotbeenstudiedin

clinicaltrials.

Fordosesnotrealisable/practicablewiththisstrengthotherstrengthsofthismedicinalproductareavailable.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer’s

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofdonepezilhydrochlorideisseen.No

reboundeffecthasbeendetectedafteranabruptdiscontinuationofitsadministration.

Renalandhepaticimpairment

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

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Children

Donepezilhydrochlorideisnotrecommendedforuseinchildren.

4.3Contraindications

Donepezilhydrochlorideiscontraindicatedinpatientswithhypersensitivitytodonepezilhydrochloride,piperidine

derivates,ortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

TheefficacyofdonepezilinpatientswithsevereAlzheimer’sdementia,othertypesofdementiaorothertypesof

memoryimpairment(e.g.age-relatedcognitivedecline),hasnotyetbeenestablished.

Anaesthesia

Donepezilhydrochlorideasacholinesteraseinhibitorislikelytoexaggeratesuccinylcholine-typemusclerelaxation

duringanaesthesia.

Cardiovascularconditions

Becauseoftheirpharmacologicalaction,cholinesteraseinhibitorsmayhavevagotoniceffectsonheartrate(e.g.,

bradycardia).Thepotentialforthisactionmaybeparticularlyimportanttopatientswith“sicksinussyndrome”orother

supraventricularcardiacconductionconditions,suchassinoatrialoratrioventricularblock.

Therehavebeenreportsofsyncopeandseizures.Ininvestigatingsuchpatientsthepossibilityofheartblockorlong

sinusalpausesshouldbeconsidered.

Gastrointestinalconditions

Patientsatincreasedriskfordevelopingulcers,e.g.,thosewithahistoryofulcerdiseaseorthosereceivingconcurrent

non-steroidalanti-inflammatorydrugs(NSAIDs),shouldbemonitoredforsymptoms.However,theclinicalstudies

withdonepezilshowednoincrease,relativetoplacebo,intheincidenceofeitherpepticulcerdiseaseorgastrointestinal

bleeding.

Genitourinary

Althoughnotobservedinclinicaltrialsofdonepezil,cholinomimeticsmaycausebladderoutflowobstruction.

Neurologicalconditions

Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralizedconvulsions.However,seizureactivitymay

alsobeamanifestationofAlzheimer’sdisease.

Cholinomimeticsmayhaveapotentialtoexacerbateorinduceextrapyramidalsymptoms.

Pulmonaryconditions

Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwithcaretopatientswitha

historyofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilhydrochlorideconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

antagonistsofthecholinergicsystemshouldbeavoided.

Severehepaticimpairment

Therearenodataforpatientswithseverehepaticimpairment.

MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

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Inthefirststudy,themortalityrateswere2/198(1%)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.

ThemortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumerically

higherthanintheplacebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityof

deathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelated

causes,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallserious

non-fatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegroup

relativetoplacebo.

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

dementiastudies(totaln=6888),themortalityrateintheplacebogroupsnumericallyexceededthatinthedonepezil

hydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilisnotaffectedbyconcurrentadministrationofdigoxin

orcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthatketoconazoleandquinidine,inhibitors

ofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.ThereforetheseandotherCYP3A4inhibitors,suchas

itraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecouldinhibitthemetabolismofdonepezil.

Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezilconcentrationsbyabout30%.

Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil.Since

themagnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuromuscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiac

conduction.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperi-andpostnataltoxicity(seesection5.3).The

potentialriskforhumansisunknown.

Donepezilhydrochlorideshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilisexcretedinhumanbreastmilkandthere

arenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhydrochloridehasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingdose.

Thetreatingphysicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperating

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4.8Undesirableeffects

Themostcommonadverseeventsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.Dizziness,

headaches,pain,accidentsandthecommoncoldhavealsobeenreported.Inmostcasesthesegoawaywithouthaving

tostoptreatment.

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).

*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuationof

treatment.

Systemorgan

class Very

common Common Uncommon Rare

Infectionsand

infestations Commoncold

Metabolismand

nutritiondisorders Anorexia

Psychiatric

disorders Hallucinations**

Agitation**

Aggressive

behaviour**

Nervoussystem

disorders Syncope*

Dizziness

Insomnia Seizure* Extrapyramidal

symptoms

Cardiacdisorders Bradycardia Sino-atrialblock

Atrioventricular

block

Gastrointestinal

disorders Diarrhoea

Nausea Vomiting

Abdominal

disturbance Gastrointestinal

haemorrhage

Gastricand

duodenalulcers

Hepatobiliary

disorders Liverdysfunction

including

hepatitis***

Skinand

subcutaneous

tissuedisorders Rash

Pruritus

Musculoskeletal

andconnective

tissuedisorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

Generaldisorders

andadministration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

Injury,poisoning

andprocedural

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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

maybeusedasanantidotefordonepezilhydrochlorideoverdosage.Intravenousatropinesulphatetitratedtoeffectis

recommended:aninitialdoseof1mgto2mgiv.withsubsequentdosesbaseduponclinicalresponse.Atypical

responsesinbloodpressureandheartratehavebeenreportedwithothercholinomimeticswhencoadministeredwith

quaternaryanticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/orits

metabolitescanberemovedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterase;

ATCcodeN06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymethatispresentmainlyoutsidethecentralnervoussystem.

InpatientswithAlzheimer’sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilhydrochlorideproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredin

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

acetylcholinesterase(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesin

ADAS-cog,asensitivescalewhichexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloride

toalterthecourseoftheunderlyingneuropathologyhasnotbeenstudied.Thusdonepezilhydrochloridecannotbe

consideredtohaveanyeffectontheprogressofthedisease.

Efficacyoftreatmentwithdonepezilhasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points,andnodeteriorationofCIBIC,andnodeteriorationof

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*p<0.05

**p<0.01

Donepezilhydrochlorideproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswho

werejudgedtreatmentresponders.

5.2Pharmacokineticproperties

Absorption

Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.Plasmaconcentrationsand

areaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeisapproximately70hours.

Administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.Approximatesteady-stateis

achievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezilhydrochloride

concentrationsandtherelatedpharmacodynamicactivityshowlittlevariabilityoverthecourseoftheday.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution

Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaproteinbindingofthe

activemetabolite6-O-desmethyldonepezilisnotknown.Thedistributionofdonepezilhydrochlorideinvariousbody

tissueshasnotbeendefinitivelystudied.Inhealthymalevolunteers,240hoursaftertheadministrationofasingle5mg

doseof 14

C-labelleddonepezilhydrochloride,approximately28%ofthelabelremainedunrecovered.Thissuggests

thatdonepezilhydrochlorideand/oritsmetabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion

DonepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochromeP450systemto

multiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mgdoseof 14

labelleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,waspresent

primarilyasintactdonepezilhydrochloride(30%),6-O-desmethyldonepezil(11%-onlymetabolitethatexhibits

activitysimilartodonepezilhydrochloride),donepezil–cis-N-oxide(9%),5-O-desmethyldonepezil(7%)andthe

glucuronideconjugateof5-O-desmethyldonepezil(3%).Approximately57%ofthetotaladministeredradioactivity

wasrecoveredfromtheurine(17%asunchangeddonepezil),and14.5%wasrecoveredfromthefaeces,suggesting

biotransformationandurinaryexcretionastheprimaryroutesofelimination.Thereisnoevidencetosuggest

enterohepaticrecirculationofdonepezilhydrochlorideand/oranyofitsmetabolites.

Plasmadonepezilconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjectsorin

Alzheimer’sdementiapatientsorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreed

withthoseofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteady-stateconcentrations;meanAUCby

48%andmeanC

by39%(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seesection4.9).Donepezilis

%Response

Intenttotreatpopulation

n=365 Evaluablepopulation

n=352

Placebogroup 10% 10%

DonepezilHCl5mg-Group 18%* 18%*

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Someclastogeniceffectswereobservedinvitroatconcentrationsovertlytoxictothecellsandmorethan3000times

thesteady-stateplasmaconcentrations.Noclastogenicorothergenotoxiceffectswereobservedinthemouse

micronucleusmodelinvivo.Therewasnoevidenceofoncogenicpotentialinlongtermcarcinogenicitystudiesin

eitherratsormice.

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstillbirthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seesection

4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Microcrystallinecellulose

Lowsubstitutedhydroxypropylcellulose

Magnesiumstearate

Film-coating:

OpadryY-1-7000White:hypromellose,titaniumdioxide(E171)andmacrogol400.

6.2Incompatibilities

Notapplicable.

6.3Shelflife

5years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

28or56film-coatedtabletsaresuppliedinOPA/Al/PVC//AlufoilorinPVC/PVdC//Alufoilblisterincartonbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

EGISPharmaceuticalsPLC

H-1106Budapest

Keresztúriút30-38

Hungary

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:17 th

April2009

10DATEOFREVISIONOFTHETEXT

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