ARIPEZ

Main information

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

Documents

Localization

  • Available in:
  • ARIPEZ Orodispersible Tablet 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/034/003
  • Authorization date:
  • 10-09-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aripez5mgOrodispersibleTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mgorodispersibletabletcontains5mgdonepezilhydrochlorideequivalentto4.56mgdonepezil.

Excipients:

Each5mgorodispersibletabletcontains183.82mglactoseanhydrousand0.14mgaspartame.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Orodispersibletablet

White,flatbevellededge,roundtablet,engravedwith“L5”ononesideandplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepezilhydrochlorideisindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer's

dementia.

4.2Posologyandmethodofadministration

Oraluse.

Fordosesnotrealisable/practicablewiththisstrength,otherstrengthsofthismedicinalproductareavailable.

Adults/Elderly:

Treatmentisinitiatedat5mg/day(once-a-daydosing).

Theorodispersibletabletshouldbetakenorally,intheevening,justpriortoretiring.Itshouldbeplacedonthetongue

andallowedtodisintegratebeforeswallowingwithorwithoutwater,accordingtopatientpreference.

The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinicalresponsesto

treatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobeachieved.Following

aone-monthclinicalassessmentoftreatmentat5mg/day,thedosecanbeincreasedto10mg/day(once-a-daydosing).

Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

hydrochlorideshouldonlybestartedifacaregiverisavailablewhowillregularlymonitormedicinalproductintakefor

thepatient.Maintenancetreatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.

Therefore,theclinicalbenefitofdonepezilhydrochlorideshouldbereassessedonaregularbasis.Discontinuation

shouldbeconsideredwhenevidenceofatherapeuticeffectisnolongerpresent.Individualresponsetodonepezil

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 1

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofdonepezilhydrochlorideisseen.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents:

Donepezilhydrochlorideisnotrecommendedforuseinchildrenandadolescents.

4.3Contraindications

Hypersensitivitytodonepezilhydrochloride,piperidinederivatives,ortoanyoftheexcipients(seesection4.4).

4.4Specialwarningsandprecautionsforuse

Theuseofdonepezilhydrochlorideinpatientswithseveredementia,othertypesofdementiaorothertypesofmemory

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

Anaesthesia:

Donepezilhydrochloride,asacholinesteraseinhibitor,islikelytoexaggeratesuccinylcholine-typemusclerelaxation

duringanaesthesia.

Cardiovascularconditions:

Becauseoftheirpharmacologicalaction,cholinesteraseinhibitorsmayhavevagotoniceffectsonheartrate(e.g.

bradycardia).Thepotentialforthisactionmaybeparticularlyimportanttopatientswith"sicksinussyndrome"orother

supraventricularcardiacconductionconditions,suchassinoatrialoratrioventricularblock.

Therehavebeenreportsofsyncopeandseizures.Ininvestigatingsuchpatientsthepossibilityofheartblockorlong

sinusalpausesshouldbeconsidered.

Gastrointestinalconditions:

Patientsatincreasedriskfordevelopingulcers,e.g.thosewithahistoryofulcerdiseaseorthosereceivingconcurrent

nonsteroidalanti-inflammatorydrugs(NSAIDs),shouldbemonitoredforsymptoms.However,theclinicalstudieswith

donepezilhydrochlorideshowednoincrease,relativetoplacebo,intheincidenceofeitherpepticulcerdiseaseor

gastrointestinalbleeding.

Genitourinary:

Althoughnotobservedinclinicaltrialsofdonepezilhydrochloride,cholinomimeticsmaycausebladderoutflow

obstruction.

Neurologicalconditions:

Seizures:

Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralisedconvulsions.However,seizureactivitymay

alsobeamanifestationofAlzheimer'sDisease.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 2

Pulmonaryconditions:

Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwithcaretopatientswitha

historyofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilhydrochlorideconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

antagonistsofthecholinergicsystemshouldbeavoided.

Severehepaticimpairment:

Therearenodataforpatientswithseverehepaticimpairment.

Mortalityinvasculardementiaclinicaltrials:

Threeclinicaltrialsof6months'durationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

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%)ondonepezilhydrochloride5mg,3/215(1.4%)ondonepezil

hydrochloride10mgand1/193(0.5%)onplacebo.

Inthethirdstudy,themortalityrateswere11/648(1.7%)ondonepezilhydrochloride5mgand0/326(0%)onplacebo.

ThemortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumerically

higherthanintheplacebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityof

deathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascular-related

causes,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallserious

non-fatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegroup

relativetoplacebo.

InpooledAlzheimer'sDiseasestudies(n=4146),andwhentheseAlzheimer'sDiseasestudieswerepooledwithother

dementiastudiesincludingthevasculardementiastudies(totaln=6,888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

Excipients:

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Thismedicinalproductcontainsaspartame,asourceofphenylalanine,andmaybeharmfulforpeoplewith

phenylketonuria.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezilhydrochloride.Interactionstudiesperformedinvitroshowthatketoconazoleandquinidine,

inhibitorsofCYP3A4and2D6respectively,inhibitdonepezilhydrochloridemetabolism.Thereforetheseandother

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 3

themetabolismofdonepezilhydrochloride.Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezil

hydrochlorideconcentrationsbyabout30%.Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineand

alcoholmayreducethelevelsofdonepezilhydrochloride.Sincethemagnitudeofaninhibitingorinducingeffectis

unknown,suchcombinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithagentshavinganticholinergicactivity.Thereisalsothe

potentialforsynergisticactivitywithconcomitanttreatmentinvolvingagentssuchassuccinylcholine,otherneuro-

muscularblockingagentsorcholinergicagonistsorbeta-blockingagentsthathaveeffectsoncardiacconduction.

4.6Pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilhydrochlorideinpregnantwomen.

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

potentialriskforhumansisunknown.

Donepezilhydrochlorideshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation:

Donepezilhydrochlorideisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedin

humanbreastmilkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilhydrochlorideshould

notbreast-feed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhydrochloridehasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilhydrochloridecaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthe

dose.Thetreatingphysicianshouldroutinelyevaluatetheabilityofpatientsondonepezilhydrochloridetocontinue

drivingoroperatingcomplexmachines.

4.8Undesirableeffects

Themostcommonadversereactionsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.

Adversereactionsreportedasmorethananisolatedcasearelistedbelow,bysystemorganclassandbyfrequency.

Frequenciesaredefinedasverycommon( ≥1/10),common(≥1/100to<1/10),uncommon(≥1/1,000to<1/100)rare

≥1/10,000to<1/1,000);veryrare(<1/10,000),notknown(cannotbeestimatedfromavailabledata).

Systemorgan

class Verycommon Common Uncommon Rare

Infectionsand

infestations Commoncold

Metabolismand

nutritiondisorders Anorexia

Psychiatric

disorders Hallucinations**

Agitation**

Aggressive

behaviour**

Nervoussystem

disorders Syncope*

Dizziness

Insomnia Seizure* Extrapyramidal

symptoms

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 4

Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4).

Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuation

oftreatment.

Incasesofunexplainedliverdysfunction,withdrawalofdonepezilhydrochlorideshouldbeconsidered.

4.9Overdose

Symptoms:

Theestimatedmedianlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.

Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreducedspontaneousmovement,

proneposition,staggeringgait,lacrimation,clonicconvulsions,depressedrespiration,salivation,miosis,fasciculation

andlowerbodysurfacetemperature.

Overdosagewithcholinesteraseinhibitorscanresultincholinergiccrisischaracterizedbyseverenausea,vomiting,

salivation,sweating,bradycardia,hypotension,respiratorydepression,collapseandconvulsions.Increasingmuscle

weaknessisapossibilityandmayresultindeathifrespiratorymusclesareinvolved.

Treatment:

Generalsupportivemeasuresshouldbeutilised.Tertiaryanticholinergicssuchasatropinemaybeusedasanantidote

fordonepezilhydrochlorideoverdose.Intravenousatropinesulphatetitratedtoeffectisrecommended:aninitialdose

of1.0to2.0mgintravenously(IV)withsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesinblood

pressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwithquaternary

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,

connectivetissue

andbonedisorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

Generaldisorders

andadministration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

Injuryand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 5

removedbydialysis(haemodialysis,peritonealdialysis,orhaemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-dementiaagents,anticholinesterases

ATCcode: N06DA02

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymewhichispresentmainlyoutsidethecentralnervoussystem.

Alzheimer'sDementia:

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor

10mgofdonepezilhydrochlorideproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredin

erythrocytemembranes)of63.6%and77.3%,respectivelywhenmeasuredpost-dose.Theinhibitionof

acetylcholinesterase(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesin

ADAS-cog,asensitivescalewhichexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloride

toalterthecourseoftheunderlyingneuropathologyhasnotbeenstudied.Thusdonepezilhydrochloridecannotbe

consideredtohaveanyeffectontheprogressofthedisease.

EfficacyoftreatmentofAlzheimer'sDementiawithdonepezilhydrochloridehasbeeninvestigatedinfourplacebo-

controlledtrials,2trialsof6-monthdurationand2trialsof1-yearduration.

Inthe6-monthclinicaltrial,ananalysiswasdoneattheconclusionofdonepezilhydrochloridetreatmentusinga

combinationofthreeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterview-

BasedImpressionofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLiving

SubscaleoftheClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesand

personalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders:

Response= ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC+

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale

*p<0.05;**p<0.01

Donepezilhydrochlorideproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswho

werejudgedtreatmentresponders.

5.2Pharmacokineticproperties

Absorption:

%response

Intent-to-treatpopulation

n=365 Evaluablepopulation

n=352

Placebogroup 10% 10%

DonepezilHCl5mggroup 18%* 18%*

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 6

areaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeisapproximately70hours,thus,

administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.Approximatesteady-stateis

achievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezilhydrochloride

concentrationsandtherelatedpharmacodynamicactivityshowlittlevariabilityoverthecourseoftheday.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution:

Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaproteinbindingofthe

activemetabolite6-O-desmethyldonepezilhydrochlorideisnotknown.Thedistributionofdonepezilhydrochloridein

variousbodytissueshasnotbeendefinitivelystudied.However,inamassbalancestudyconductedinhealthymale

volunteers,240hoursaftertheadministrationofasingle5mgdoseof 14

C-labelleddonepezilhydrochloride,

approximately28%ofthelabelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/orits

metabolitesmaypersistinthebodyformorethan10days.

Metabolism/excretion:

DonepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochromeP450systemto

multiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mgdoseof 14

labelleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,waspresent

primarilyasintactdonepezilhydrochloride(30%),6-O-desmethyldonepezilhydrochloride(11%-onlymetabolitethat

exhibitsactivitysimilartodonepezilhydrochloride),donepezilhydrochloride-cis-N-oxide(9%),5-O-

desmethyldonepezilhydrochloride(7%)andtheglucuronideconjugateof5-O-desmethyl-donepezilhydrochloride

(3%).Approximately57%ofthetotaladministeredradioactivitywasrecoveredfromtheurine(17%asunchanged

donepezilhydrochloride),and14.5%wasrecoveredfromthefaeces,suggestingbiotransformationandurinary

excretionastheprimaryroutesofelimination.Thereisnoevidencetosuggestenterohepaticrecirculationofdonepezil

hydrochlorideand/oranyofitsmetabolites.

Plasmadonepezilhydrochlorideconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhydrochloridehasnotbeenformallystudiedinhealthyelderly

subjectsorinAlzheimer'sorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwith

thoseofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilhydrochloridesteadystateconcentrations;

meanareaunderthecurveby48%andmeanpeakplasmaconcentrationsby39%(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seesection4.9).

Donepezilhydrochlorideisnotmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffects

wereobservedinvitroatconcentrationsovertlytoxictothecellsandmorethan3,000timesthesteady-stateplasma

concentrations.Noclastogenicorothergenotoxiceffectswereobservedinthemousemicronucleusmodelinvivo.

Therewasnoevidenceofoncogenicpotentialinlongtermcarcinogenicitystudiesineitherratsormice.

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstill-birthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seesection

4.6).

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 7

6.1Listofexcipients

Mannitol(E421)

Hypromellose

Silical,colloidalanhydrous

Crospovidone

Lactosemonohydrate

Maizestarch

Aspartame(E951)

Magnesiumstearate

6.2Incompatibilities

Notapplicable

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Blister(OPA/Alu/PVC–Aluminium(peel-off)blisters),regularandcalendarpacks

Packsizes:1,7,28,30,50,56,60,98,100or120orodispersibletablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

Netherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/34/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10September2010

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/09/2010 CRN 2057214 page number: 8