ARIPEZ

Main information

  • Trade name:
  • ARIPEZ Tablets 5 Milligram
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARIPEZ Tablets 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/034/001
  • Authorization date:
  • 01-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aripez5mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgdonepezilhydrochloride,equivalentto4.56mgdonepezil.

Excipient:128.2mglactose/tablet

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Film-CoatedTablet.

WhiteFilm-Coatedovalshapedtablets,debossedwith"93"ononesideand"7320"ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AripeztabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer'sdementia.

4.2Posologyandmethodofadministration

Oraluse.

Adults/Elderly:

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

retiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinicalresponses

totreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobeachieved.

Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseofdonepezilcanbeincreasedto10

mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenot

beenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofDonepezilisseen.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

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Childrenandadolescents:

Donepezilisnotrecommendedforuseinchildrenandadolescents.

4.3Contraindications

Donepeziliscontraindicatedinpatientswithaknownhypersensitivitytodonepezilhydrochloride,piperidine

derivatives,ortoanyoftheexcipients(seesection4.4).

4.4Specialwarningsandprecautionsforuse

TheuseofdonepezilinpatientswithsevereAlzheimer'sdementia,othertypesofdementiaorothertypesofmemory

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

Anaesthesia:Donepezil,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,theclinicalstudieswithdonepezilshowednoincrease,relativetoplacebo,intheincidenceofeitherpeptic

ulcerdiseaseorgastrointestinalbleeding.

Genitourinary:Althoughnotobservedinclinicaltrialsofdonepezil,cholinomimeticsmaycausebladderoutflow

obstruction.

NeurologicalConditions:Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsorantagonistsof

thecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorbtionshouldnottakethismedicinalproduct.

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.

ThemortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumerically

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Themajorityofdeathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvarious

vascularrelatedcauses,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.An

analysisofallseriousnonfatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezil

hydrochloridegrouprelativetoplacebo.

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdoesnotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthatketoconazoleandquinidine,inhibitors

ofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.ThereforetheseandotherCYP3A4inhibitors,suchas

itraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecouldinhibitthemetabolismofdonepezil.

Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezilconcentrationsbyabout30%.Enzyme

inducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil.Sincethe

magnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuro-muscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiac

conduction.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperi-andpost-nataltoxicity(seesection5.3).The

potentialriskforhumansisunknown.

Donepezilshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.Dementiamaycauseimpairment

ofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,donepezilcaninducefatigue,

dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreatingphysicianshouldroutinely

evaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplexmachines.

4.8Undesirableeffects

Themostcommonadverseeventsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.

Adversereactionsreportedasmorethananisolatedcasearelistedbelow,bysystemorganclassandbyfrequency.

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

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuationof

treatment.

SystemOrganClass Verycommon Common Uncommon Rare

Infectionsand

infestations Commoncold

Metabolismand

nutritiondisorders Anorexia

Psychiatricdisorders 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

Hepato-biliary

disorders Liverdysfunction

including

hepatitis***

Skinand

subcutaneoustissue

disorders Rash

Pruritis

Musculoskeletal,

connectivetissueand

bonedisorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

Generaldisordersand

administrationsite

conditions Headache Fatigue

Pain

Investigations Minorincreasein

serumconcentration

ofmusclecreatine

kinase

Injury,poisoningand

procedural

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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

maybeusedasanantidotefordonepeziloverdosage.Intravenousatropinesulphatetitratedtoeffectisrecommended:

aninitialdoseof1.0to2.0mgintravenouslywithsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesin

bloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwithquaternary

anticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/oritsmetabolitescanbe

removedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anticholinesterases

ATCcode:N06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymewhichispresentmainlyoutsidethecentralnervoussystem.

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocytemembranes)

of63.6%and77.3%,respectivelywhenmeasuredpostdose.Theinhibitionofacetylcholinesterase(AChE)inred

bloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesinADAS-cog,asensitivescalewhich

examinesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloridetoalterthecourseoftheunderlying

neuropathologyhasnotbeenstudied.Thusdonepezilcannotbeconsideredtohaveanyeffectontheprogressofthe

disease.

Efficacyoftreatmentwithdonepezilhasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-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 %Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Donepezil5-mgGroup 18%* 18%*

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Donepezilproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowerejudged

treatmentresponders.

5.2Pharmacokineticproperties

Generalcharacteristics

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 14

C-labelleddonepezilhydrochloride,

approximately28%ofthelabelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/orits

metabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion:Donepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochrome

P450systemtomultiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mg

doseof 14

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'spatientsorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwiththose

ofyounghealthyvolunteers.

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

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core

Lactoseanhydrous

Microcrystallinecellulose

Pregelatinizedmaizestarch

Hypromellose

Magnesiumstearate

Coating

Polyvinylalcohol

Titaniumdioxide(E171)

Macrogol3350

Talc

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

TransparentPVC/PVdC–Aluminiumblister.

Packsizes:

1,7,14,28,30,50,56,60,84,98,and120film-coatedtablets.

Hospitalpacks:50(50x1)film-coatedtablets.

Calendarpacks:28,56and98film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

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7MARKETINGAUTHORISATIONHOLDER

TEVAPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA0749/034/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

1stFebruary2008

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