ARICEPT

Main information

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

Documents

Localization

  • Available in:
  • ARICEPT Film Coated Tablet 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1562/018/001
  • Authorization date:
  • 12-02-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1562/018/001

CaseNo:2073602

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

LTTPharmaLimited

Unit18,OxleasowRoad,EastMoonMoat,Redditch,WorcestershireB980RE,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Aricept5mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom12/02/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 17/02/2010 CRN 2073602 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aricept5mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgdonepezilhydrochloride,equivalentto4.56mgdonepezilfreebase.

Alsocontainslactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-CoatedTablets

ProductimportedfromItaly:

White,round,biconvextablets.

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/dayhavenotbeenstudiedinclinicaltrials.

Treatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisand

treatmentofAlzheimer’sdementia.Diagnosisshouldbemadeaccordingtoacceptedguidelines(e.g.DSMIV,ICD

10).Therapywithdonepezilshouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakefor

thepatient.Maintenancetreatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.

Therefore,theclinicalbenefitofdonepezilshouldbereassessedonaregularbasis.Discontinuationshouldbe

consideredwhenevidenceofatherapeuticeffectisnolongerpresent.Individualresponsetodonepezilcannotbe

predicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofARICEPTisseen.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

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Children:

ARICEPTisnotrecommendedforuseinchildren.

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.

TheadministerationofARICEPTconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsorantagonists

ofthecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDSAIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

dementiaappearstobeduesolelytovascularcausesandtoexcludepatientswithAlzheimer’sdisease.

Inthefirststudy,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

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ThemortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumerically

higherthanintheplacebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityof

deathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelated

causes,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallserious

nonfatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegroup

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,carbamazepineandalcoholmayreducethelevelsofdonepezil.

Sincethemagnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuro-muscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiac

conduction.

4.6Pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

Ariceptshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation:

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

machines.

4.8Undesirableeffects

Themostcommonadverseeventsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.Adverse

reactionsreportedasmorethananisolatedcasearelistedbelow,bysystemorganclassandbyfrequency.Frequencies

aredefinedas:verycommon(>1/10)common(>1/100,<1/10),uncommon(>1/1,000,<1/100),andrare(>

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviorhaveresolvedondose-reductionordiscontinuationof

treatment.

System Organ

Class Very

Common Common Uncommon Rare

Infectionsand Commoncold

infestations

Metabolismand Anorexia

nutrition

disorders

Psychiatric Hallucinations**

disorders Agitation**

Aggressive

behaviour**

Nervous system

disorders Syncope*

Dizziness

Insomnia Seizure* Extrapyramidal

symptoms

Cardiacdisorders Bradycardia Sino-atrialblock

Atrioventricular

block

Gastrointestinal Diarrhoea

Vomiting

Abdominal

disturbance Gastrointestinal

disorders Nausea haemorrhage

Gastricand

duodenalulcers

Hepato-biliary Liver

dysfunction

disorders including

hepatitis***

Skinand Rash

subcutaneous Pruritis

tissuedisorders

Musculoskeletal, Musclecramps

connectivetissue

andbone

disorders

Renalandurinary Urinary

incontinence disorders

Generaldisorders Headache

Fatigue

Pain and

administration

site

conditions

Investigations Minorincrease

inserum

concentrationof

musclecreatine

kinase

Injuryand Accident

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4.9Overdose

Theestimatedmedianlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreduced

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

salivation,miosis,fasciculationandlowerbodysurfacetemperature.Overdosagewithcholinesteraseinhibitorscan

resultincholinergiccrisischaracterizedbyseverenausea,vomiting,salivation,sweating,bradycardia,hypotension,

respiratorydepression,collapseandconvulsions.Increasingmuscleweaknessisapossibilityandmayresultindeathif

respiratorymusclesareinvolved.Asinanycaseofoverdose,generalsupportivemeasuresshouldbeutilised.Tertiary

anticholinergicssuchasatropinemaybeusedasanantidoteforARICEPToverdosage.Intravenousatropinesulphate

titratedtoeffectisrecommended:aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinical

response.Atypicalresponsesinbloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-

administeredwithquaternaryanticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochloride

and/oritsmetabolitescanberemovedbydialysis(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.ThusAriceptcannotbeconsideredtohaveanyeffectontheprogressofthe

disease.

EfficacyoftreatmentwithAricepthasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6monthduration

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

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

metabolitesmaypersistinthebodyformorethan10days.

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%ofthetotaladministeredradioactivitywasrecoveredfromtheurine(17%asunchanged

donepezil),and14.5%wasrecoveredfromthefaeces,suggestingbiotransformationandurinaryexcretionasthe

primaryroutesofelimination.Thereisnoevidencetosuggestenterohepaticrecirculationofdonepezilhydrochloride

and/oranyofitsmetabolites.Plasmadonepezilconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjectsorin

Alzheimer’sorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwiththoseofyoung

healthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteadystateconcentrations;meanAUCby

%Response

IntenttoTreat

Population

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Aricept5-mgGroup 18%* 18%*

Aricept10-mg 21%* 22%**

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5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seesection4.9).

Donepezilisnotmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffectswereobserved

invitroatconcentrationsovertlytoxictothecellsandmorethan3000timesthesteady-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

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterpacksof28tabletscontainedinanoverlabelledoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7ParallelProductAuthorisationHolder

LTTPharmaLimited

Unit18OxleasowRoad

EastMoonMoat

Redditch

WorcestershireB980RE

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1562/18/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12 th

February2010

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