DENTAP

Main information

  • Trade name:
  • DENTAP Film Coated Tablet 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DENTAP Film Coated Tablet 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/044/002
  • Authorization date:
  • 27-11-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DonepezilTeva10mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains10mgdonepezilhydrochloride

Excipient(s):

Each10mgfilm-coatedtabletcontains113.89mgoflactose(asmonohydrate)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

DonepezilTeva10mgfilm-coatedtabletsareyellow,round,biconvexfilm-coatedtablets,withbevelededgesand

debossed'TEVA'ononesideand739ontheotherside

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepezilTevafilm-coatedtabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevere

Alzheimer'sdementia.

4.2Posologyandmethodofadministration

Oraluse.

Fordosesnotrealisable/practicablewiththisstrengthotherstrengthsofthismedicinalproductareavailable.

Adults/Elderly:

Treatmentisinitiatedat5mg/day(once-a-daydosing).Donepezilhydrochlorideshouldbetakenorally,inthe

evening,justpriortoretiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowthe

earliestclinicalresponsestotreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezil

hydrochloridetobeachieved.Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseof

donepezilhydrochloridecanbeincreasedto10mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis

10mg.Dosesgreaterthan10mg/dayhavenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

hydrochlorideshouldonlybestartedifacaregiverisavailablewhowillregularlymonitormedicinalproductintakefor

thepatient.Maintenancetreatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,

theclinicalbenefitofdonepezilhydrochlorideshouldbereassessedonaregularbasis.

Discontinuationshouldbeconsideredwhenevidenceofatherapeuticeffectisnolongerpresent.Individualresponseto

donepezilhydrochloridecannotbepredicted.

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Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents:

Donepezilhydrochlorideisnotrecommendedforuseinchildrenandadolescents.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients,ortopiperidinederivatives.

4.4Specialwarningsandprecautionsforuse

TheuseofdonepezilhydrochlorideinpatientswithsevereAlzheimer'sdementia,othertypesofdementiaorother

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

Anaesthesia:Donepezilhydrochloride,asacholinesteraseinhibitor,islikelytoexaggeratesuccinylcholine-type

musclerelaxationduringanaesthesia.

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:Althoughnotobservedinclinicaltrialsofdonepezilhydrochloride,cholinomimeticsmaycause

bladderoutflowobstruction.

NeurologicalConditions:Seizures:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms.

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilhydrochlorideconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

antagonistsofthecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

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MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

dementiaappearstobeduesolelytovascularcausesandtoexcludepatientswithAlzheimer'sdisease.Inthefirststudy,

themortalityrateswere2/198(1.0%)ondonepezilhydrochloride5mg,5/206(2.4%)ondonepezilhydrochloride10

mgand7/199(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.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezilhydrochloride.Druginteractionstudiesperformedinvitroshowthatketoconazoleand

quinidine,inhibitorsofCYP3A4and2D6respectively,inhibitdonepezilhydrochloridemetabolism.Thereforethese

andotherCYP3A4inhibitors,suchasitraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecould

inhibitthemetabolismofdonepezilhydrochloride.Inastudyinhealthyvolunteers,ketoconazoleincreasedmean

donepezilhydrochlorideconcentrationsbyabout30%.

Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil

hydrochloride.Sincethemagnitudeofaninhibitingorinducingeffectisunknown,suchmedicinalproduct

combinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuro-muscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiac

conduction.

4.6Fertility,pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofdonepezilhydrochlorideinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperiandpostnataltoxicity(seesection5.3

preclinicalsafetydata).Thepotentialriskforhumansisunknown.

Donepezilhydrochlorideshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation:

Donepezilhydrochlorideisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedin

humanbreastmilkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilhydrochlorideshould

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4.7Effectsonabilitytodriveandusemachines

Donepezilhydrochloridehasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilhydrochloridecaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthe

dose.Thetreatingphysicianshouldroutinelyevaluatetheabilityofpatientsondonepezilhydrochloridetocontinue

drivingoroperatingcomplexmachines.

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

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

SystemOrganClass VeryCommon Common Uncommon Rare

Infectionsandinfestations Commoncold

Metabolismandnutrition

disorders Anorexia

Psychiatricdisorders Hallucinations**

Agitation**

Aggressive

behaviour**

Nervoussystemdisorders Syncope*

Dizziness

Insomnia Seizure* Extrapyramidal

symptoms

Cardiacdisorders Bradycardia Sino-atrialblock

Atrioventricular

block

Gastrointestinaldisorders Diarrhoea

Nausea Vomiting

Abdominal

disturbance Gastrointestinal

haemorrhage

Gastricand

duodenalulcers

Hepato-biliarydisorders Liver

dysfunction

including

hepatitis***

Skinandsubcutaneoustissue

disorders Rash

Pruritis

Musculoskeletal,connective

tissueandbonedisorders Musclecramps

Renalandurinarydisorders Urinary

incontinence

Generaldisordersand

administrationsiteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuationof

treatment.

***Incasesofunexplainedliverdysfunction,withdrawalofdonepezilhydrochlorideshouldbeconsidered.

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:

aninitialdoseof1.0to2.0mgIVwithsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesinblood

pressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwithquaternary

anticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/oritsmetabolitescanbe

removedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterase,ATCcode:N06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymethatispresentmainlyoutsidethecentralnervoussystem.

Alzheimer'sDementia

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocytemembranes)

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

bloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesinADAS-cog,asensitivescalewhich

examinesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloridetoalterthecourseoftheunderlying

neuropathologyhasnotbeenstudied.Thusdonepezilcannotbeconsideredtohaveanyeffectontheprogressofthe

disease.

Efficacyoftreatmentwithdonepezilhydrochloridehasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-

monthdurationand2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepezilhydrochloridetreatmentusinga

combinationofthreeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterview

BasedImpressionofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLiving

SubscaleoftheClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesand

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Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

*p<0.05

**p<0.01

Donepezilhydrochlorideproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswho

werejudgedtreatmentresponders.

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,

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.

Response= ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC+

NoDeteriorationofActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Donepezil5-mgGroup 18%* 18%*

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Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhydrochloridehasnotbeenformallystudiedinhealthyelderly

subjectsorinAlzheimer'sorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwith

thoseofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilhydrochloridesteadystateconcentrations;

meanAUCby48%andmeanC

by39%(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seeSection4.9).Donepezil

hydrochlorideisnotmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffectswere

observedinvitroatconcentrationsovertlytoxictothecellsandmorethan3000timesthesteady-stateplasma

concentrations.Noclastogenicorothergenotoxiceffectswereobservedinthemousemicronucleusmodelinvivo.

Therewasnoevidenceofoncogenicpotentialinlongtermcarcinogenicitystudiesineitherratsormice.

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstillbirthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seeSection

4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Maizestarch

Lactosemonohydrate

Cellulose,microcrystalline

Sodiumstarchglycolate,typeA

Silica,colloidalanhydrous

Magnesiumstearate

Filmcoating:

OpadryII31F32561yellowconsistingof:

Lactosemonohydrate

Hypromellose15cp

Titaniumdioxide(E171)

Macrogol4000

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

OPA25µm/Al45µm/PVC60µm//Alblisters

Packsizes:7,28,30,50,56,60,84,90,98or120tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLimited

VisionHouse

BedfordRoad

Petersfield

Hampshire

GU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA585/44/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27thNovember2009

10DATEOFREVISIONOFTHETEXT

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