ARICEPT 5 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • ARICEPT 5 MG FILM-COATED TABLETS
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARICEPT 5 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/108/001A
  • Authorization date:
  • 19-09-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aricept5mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgdonepezilhydrochloride.

Excipients:Lactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromFrance,Greece,SpainandItaly:

White,round,biconvextabletswith‘ARICEPT’ononesideand‘5’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.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofARICEPTisseen.Thereisno

evidenceofareboundeffectafterabruptdiscontinuationoftherapy.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairmentasclearanceofclearanceofdonepezil

hydrochlorideisnotaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Children:

ARICEPTisnotrecommendedforuseinchildren.

4.3Contraindications

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derivatives,ortoanyexcipientsusedintheformulation.ARICEPTiscontraindicatedinpregnancy.

Ariceptincludeslactose.Patientwithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyor

glucose-galactosemalabsorptionshouldnottakethismedicine.

4.4Specialwarningsandprecautionsforuse

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.

Therefore,theclinicalbenefitofdonepezilshouldbereassessedonaregularbasis.Discontinuationshouldbe

consideredwhenevidenceofatherapeuticeffectisnolongerpresent.Individualresponsetodonepezilcannotbe

predicted.TheuseofARICEPTinpatientswithsevereAlzheimer'sdementia,othertypesofdementiaorothertypesof

memoryimpairment(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.

HepaticImpariment:Therearenodataforpatientswithseverehepaticimpairment.

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.TheadministrationofARICEPT

concomitantlywithotherinhibitorsofacetylcholinesterase,agonistsorantagonistsofthecholinergicsystemshouldbe

avoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdoesnotinhibitthemetabolismoftheophylline,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.

4.6Fertility,pregnancyandlactation

Pregnancy:

Teratologystudiesconductedinpregnantratsatdosesuptoapproximately80timesthehumandoseandinpregnant

rabbitsatdosesuptoapproximately50timesthehumandosedidnotdiscloseanyevidenceforateratogenicpotential.

However,inastudyinwhichpregnantratsweregivenapproximately50timesthehumandosefromday17of

gestationthroughday20postpartum,therewasaslightincreaseinstillbirthsandaslightdecreaseinpupsurvival

throughday4postpartum.Noeffectwasobservedatthenextlowerdosetested,approximately15timesthehuman

dose.ARICEPTshouldnotbeusedduringpregnancy.Fordonepezilnoclinicaldataonexposedpregnanciesare

available.

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.

Frequenciesaredefinedas:verycommon(>1/10),common(>1/100,<1/10),uncommon(>1/1,000,<1/100),rare

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Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

Reportsofhallucinations,agitationandaggressivebehaviourhaveredolvedondose-reductionordiscontinuationof

treatment.

Incaseofunexplainedliverdysfunction,withdrawlofARICEPTshouldbeconsidered.

4.9Overdose

Theestimatedmedianlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreduced

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

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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:antidementia;drugsanticholinesterase;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.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC

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*p<0.05

**p<0.01

Ariceptproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowerejudged

treatmentresponders.

5.2Pharmacokineticproperties

Generalcharacteristics

Absorption:

Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.Plasmaconcentrationsand

areaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeisapproximately70hours,thus,

administrationofmultiplesingle-dailydosesresultsingradual

approachtosteady-state.Approximatesteady-stateisachievedwithin3weeksafterinitiationoftherapy.Onceat

steady-state,plasmadonepezilhydrochlorideconcentrationsandtherelatedpharmacodynamicactivityshowlittle

variabilityoverthecourseoftheday.Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution:

Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaproteinbindingofthe

activemetabolite6-O-desmethyldonepezilisnotknown.Thedistributionofdonepezilhydrochlorideinvariousbody

tissueshasnotbeendefinitivelystudied.However,inamassbalancestudyconductedinhealthymalevolunteers,240

hoursaftertheadministrationofasingle5mgdoseof 14

C-labelleddonepezilhydrochloride,approximately28%ofthe

labelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/oritsmetabolitesmaypersistinthebody

formorethan10days.

Metabolism/Excretion:

DonepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochromeP450systemto

multiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mgdoseof 14

labeleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentageoftheadministereddose,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.

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Metabolism/Excretion

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

Microcrystallinecellulose

Hyprolose

Magnesiumstearate

Filmcoating

Talc

Macrogol

Hypromellose

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialinstructions.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA0465/108/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorizations:19September2003

Dateoflastrenewal:19September2008

10DATEOFREVISIONOFTHETEXT

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