DONEPEZIL PFIZER

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/076/001
  • Authorization date:
  • 21-10-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DonepezilPfizer5mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains5mgdonepezilhydrochloride,equivalentto4.56mgofdonepezilfreebase.

87.17mglactose/film-coatedtablet

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whiteround,biconvexfilm-coatedtabletsembossed‘5’ononeside

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepezilPfizerfilm-coatedtabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevere

Alzheimer’sdementia.

4.2Posologyandmethodofadministration

Adults/Elderly:

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

priortoretiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinical

responsestotreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobe

achieved.Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseofDonepezilPfizercanbe

increasedto10mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10

mg/dayhavenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer’s

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofDonepezilPfizerisseen.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents:

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4.3Contraindications

DonepezilPfizeriscontraindicatedinpatientswithaknownhypersensitivitytodonepezilhydrochloride,piperidine

derivatives,ortoanyexcipientsusedintheformulation

4.4Specialwarningsandprecautionsforuse

TheuseofDonepezilPfizerinpatientswithsevereAlzheimer’sdementia,othertypesofdementiaorothertypesof

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

Anaesthesia:DonepezilPfizer,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,theclinicalstudieswithDonepezilPfizershowednoincrease,relativetoplacebo,intheincidenceofeither

pepticulcerdiseaseorgastrointestinalbleeding.

Genitourinary:AlthoughnotobservedinclinicaltrialsofDonepezilPfizer,cholinomimeticsmaycausebladder

outflowobstruction.

NeurologicalConditions:Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

TheadministerationofDonepezilPfizerconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

antagonistsofthecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

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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.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.Thereisalsothepotentialforsynergisticactivitywithconcomitanttreatmentinvolving

medicationssuchassuccinylcholine,otherneuro-muscularblockingagentsorcholinergicagonistsorbetablocking

agentswhichhaveeffectsoncardiacconduction.

4.6Fertility,pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

DonepezilPfizershouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation:

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

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4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

machines.

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(<1/10000)andnotknown(cannotbeestimatedfromavailabledata).

SystemOrgan

Class VeryCommon Common Uncommon Rare

Infectionsand

infestations Commoncold

Metabolismand

nutrition

disorders Anorexia

Psychiatric

disorders Hallucinations**

Agitation**

Aggressive

behaviour**

Abnormal

dreamsand

Nighmares**

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

Hepato-biliary

disorders Liver

dysfunction

including

hepatitis***

Skinand

subcutaneous

tissuedisorders Rash

Pruritis

Musculoskeletal,

connectivetissue

andbone

disorders Musclecramps

Renaland

urinarydisorders Urinary

incontinence

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,abnormaldreams,nightmares,agitationandaggressivebehaviourhaveresolvedondose-

reductionordiscontinuationoftreatment.

***Incasesofunexplainedliverdysfunction,withdrawalofDonepezilPfizershouldbeconsidered.

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

maybeusedasanantidoteforDonepezilPfizeroverdosage.Intravenousatropinesulphatetitratedtoeffectis

recommended:aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypical

responsesinbloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwith

quaternaryanticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/orits

metabolitescanberemovedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

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

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymethatispresentmainlyoutsidethecentralnervoussystem.

Alzheimer’sDementia

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofDonepezilPfizerproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocyte

membranes)of63.6%and77.3%,respectivelywhenmeasuredpostdose.Theinhibitionofacetylcholinesterase

(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesinADAS-cog,asensitive

scalewhichexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloridetoalterthecourseofthe

underlyingneuropathologyhasnotbeenstudied.ThusDonepezilPfizercannotbeconsideredtohaveanyeffectonthe

administration

siteconditions Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

Injuryand

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EfficacyoftreatmentwithDonepezilPfizerhasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-month

durationand2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response= ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC+

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale

*p<0.05

**p<0.01

DonepezilPfizerproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowere

judgedtreatmentresponders.

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-desmethyldonepezilisnotknown.Thedistributionofdonepezilhydrochloridein

variousbodytissueshasnotbeendefinitivelystudied.However,inamassbalancestudyconductedinhealthymale

volunteers,240hoursaftertheadministrationofasingle5mgdoseof C-labeleddonepezilhydrochloride,

approximately28%ofthelabelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/orits

%Response

IntenttoTreat

Population

n=365 Evaluable

Population

n=352

PlaceboGroup 10% 10%

DONEPEZILtablets

5-mgGroup 18%* 18%*

DONEPEZILtablets

10-mgGroup 21%* 22%**

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Metabolism/Excretion:Donepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochrome

P450systemtomultiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mg

doseof C-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.

Plasmadonepezilconcentrationsdeclinewithahalf -lifeofapproximately70hours.

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

Lactosemonohydrate

Maizestarch

Cellulose,microcrystalline

Hyprolose

MagnesiumStearate.

Filmcoating

Talc

Macrogol,

Hypromellose

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Bottles(HDPE)of28,30and100

Blister(PVC/Aluminium)

Packsizes:7,14,28,30,50,56,60,84,98,112or120tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk,

NationalDigitalPark,

CitywestBusinessCampus,

Dublin24,

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/76/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21stOctober2011

10DATEOFREVISIONOFTHETEXT

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