DONEPEZIL KRKA

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1347/014/001
  • Authorization date:
  • 20-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DonepezilKrka5mgOrodispersibletablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachorodispersibletabletcontainsdonepezilhydrochloridemonohydrateequivalentto5mgdonepezilhydrochloride.

Excipient:

Eachorodispersibletabletcontains0.75mgaspartame(E951),0.30mgglucose,0.25mgsucroseand0.02mgsorbitol

(E420).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Orodispersibletablet.

Whiteroundorodispersibletablets,bevel-edged.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepezilKrka5mgOrodispersibletabletsisindicatedforthesymptomatictreatmentofmildtomoderatelysevere

Alzheimer'sdementia.

4.2Posologyandmethodofadministration

Adults/Elderly:

Treatmentisinitiatedat5mg/day(once-a-daydosing).DonepezilKrka5mgOrodispersibletabletsshouldbetaken

orally,intheevening,justpriortoretiring.Thetabletshouldbeplacedonthetongueandallowedtodisintegratebefore

swallowingwithorwithoutwater,accordingtopatientpreference.The5mg/daydoseshouldbemaintainedforatleast

onemonthinordertoallowtheearliestclinicalresponsestotreatmenttobeassessedandtoallowsteady-state

concentrationsofdonepezilhydrochloridetobeachieved.Followingaone-monthclinicalassessmentoftreatmentat

5mg/day,thedoseofDonepezilKrka5mgOrodispersibletabletscanbeincreasedto10mg/day(once-a-daydosing).

Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofDonepezilKrka5mgOrodispersible

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Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents:

DonepezilKrka5mgOrodispersibletabletsisnotrecommendedforuseinchildrenandadolescentsbelow18yearsof

age.

4.3Contraindications

DonepezilKrka5mgOrodispersibletabletsiscontraindicatedinpatientswithaknownhypersensitivitytodonepezil

hydrochloride,piperidinederivatives,ortoanyexcipientsusedintheformulation.

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,theclinicalstudieswithdonepezilhydrochlorideshowednoincrease,relativetoplacebo,intheincidenceof

eitherpepticulcerdiseaseorgastrointestinalbleeding.

Genitourinary:Althoughnotobservedinclinicaltrialsofdonepezil,cholinomimeticsmaycausebladderoutflow

obstruction.

NeurologicalConditions:Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

TheadministrationofDonepezilKrka5mgOrodispersibletabletsconcomitantlywithotherinhibitorsof

acetylcholinesterase,agonistsorantagonistsofthecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

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themortalityrateswere2/198(1.0%)ondonepezilhydrochloride5mg,5/206(2.4%)ondonepezilhydrochloride

10mgand7/199(3.5%)onplacebo.Inthesecondstudy,themortalityrateswere4/208(1.9%)ondonepezil

hydrochloride5mg,3/215(1.4%)ondonepezilhydrochloride10mgand1/193(0.5%)onplacebo.Inthethirdstudy,

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

forthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumericallyhigherthaninthe

placebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityofdeathsinpatients

takingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelatedcauses,whichcouldbe

expectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallseriousnon-fatalandfatal

vasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegrouprelativetoplacebo.

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

ImportantinformationonsomeothercomponentsofDonepezilKrka5mgOrodispersibletablets:

Aspartame(E951):

Containsasourceofphenylalanine.Maybeharmfulforpeoplewithphenylketonuria.

Glucose(dextrose):

Patientswithrareglucose-galactosemalabsorptionshouldnottakethismedicine.

Sucrose:

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

Sorbitol(E420):

Patientswithrarehereditaryproblemsoffructoseintoleranceshouldnottakethismedicine.

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,carbamazepineandalcoholmayreduce

thelevelsofdonepezil.Sincethemagnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinations

shouldbeusedwithcare.Donepezilhydrochloridehasthepotentialtointerferewithmedicationshaving

anticholinergicactivity.Thereisalsothepotentialforsynergisticactivitywithconcomitanttreatmentinvolving

medicationssuchassuccinylcholine,otherneuro-muscularblockingagentsorcholinergicagonistsorbetablocking

agentsthathaveeffectsoncardiacconduction.

4.6Fertility,pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

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Lactation:

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

machines.

4.8Undesirableeffects

Themostcommonadversereactionsarediarrhoea,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).

SystemOrganClass Very

Common 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

Gastricandduodenal

ulcers

Hepatobiliary

disorders Liverdysfunction

including

hepatitis***

Skinand

subcutaneoustissue

disorders Rash

Pruritis

Musculoskeletal,

connectivetissueand

bonedisorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuation

oftreatment.

***Incasesofunexplainedliverdysfunction,withdrawalofdonepezilshouldbeconsidered.

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

maybeusedasanantidotefor

DonepezilKrka5mgOrodispersibletabletsoverdosage.Intravenousatropinesulphatetitratedtoeffectis

recommended:aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypical

responsesinbloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwith

quaternaryanticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/orits

metabolitescanberemovedbydialysis(haemodialysis,peritonealdialysis,orhaemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs,anticholinesterase

ATCcode:N06DA02

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymewhichispresentmainlyoutsidethecentralnervoussystem.

Alzheimer'sDementia

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor

10mgof[Productname]producedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocyte

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

(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesinADAS-cog,asensitive

scalewhichexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloridetoalterthecourseofthe

underlyingneuropathologyhasnotbeenstudied.Thus[Productname]cannotbeconsideredtohaveanyeffectonthe

andadministration

siteconditions Pain

Investigations Minorincreasein

serumconcentration

ofmusclecreatine

kinase

Injuryandpoisoning

andprocedural

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EfficacyoftreatmentofAlzheimer'sDementiawithdonepezilhasbeeninvestigatedinfourplacebo-controlledtrials,2

trialsof6-monthdurationand2trialsof1-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

Donepezilproducedadose-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 14

C-labelleddonepezilhydrochloride,

approximately28%ofthelabelremainedunrecovered.Thissuggeststhatdonepezilhydrochlorideand/orits

metabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion:Donepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochrome

P450systemtomultiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mg

doseof 14

C-labelleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Donepezil5-mgGroup 18%* 18%*

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exhibitsactivitysimilartodonepezilhydrochloride),donepezil-cis-N-oxide(9%),5-O-desmethyldonepezil(7%)and

theglucuronideconjugateof5-O-desmethyl-donepezil(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

effectonstill-birthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seesection

4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Cellulose,microcrystalline

Hydroxypropylcellulose,low-substituted

Maltodextrine

Dextrose

Sucrose

Gumarabic

Sorbitol(E420)

Flavouring,banana

Aspartame(E951)

Calciumsilicate

Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

Storeintheoriginalblisterinordertoprotectfrommoisture.Thismedicinalproductdoesnotrequireanyspecial

temperaturestorageconditions.

6.5Natureandcontentsofcontainer

Blisters(OPA/Al/PVCfilmandpeel-openPET/Alfoil)of10,28,30,50,56,60,84,90,98and100orodispersible

tabletsinacardboardbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Krkad.d.

Novomesto

Šmarješkacesta

8501Novomesto

Slovenia

8MARKETINGAUTHORISATIONNUMBER

PA1347/14/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20May2011

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