DONEPEZIL HYDROCHLORIDE RANBAXY

Main information

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

Documents

Localization

  • Available in:
  • DONEPEZIL HYDROCHLORIDE RANBAXY
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/077/002
  • Authorization date:
  • 13-11-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DonepezilHydrochlorideRanbaxy10mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgdonepezilhydrochloride,equivalentto9.12mgdonepezil.

Excipient:

Eachfilm-coated10mgtabletalsocontains166.29mgLactose

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Yellowcoloured,capsuleshaped,film-coatedtabletsdebossedwith‘RC’ononesideofthescorelineand26onother

side

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonepeziltabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer'sdementia.

4.2Posologyandmethodofadministration

Oraluse

Adults/Elderly:

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

justpriortoretiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliest

clinicalresponsestotreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobe

achieved.Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseofdonepezilcanbeincreased

to10mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/day

havenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofDonepezilisseen.

Fordosesnotrealisable/practicablewiththismedicinalproductanotherstrengthofthismedicinalproductisavailable

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

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Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents:

Donepezilisnotrecommendedforuseinchildren.

4.3Contraindications

DonepezilHydrochlorideiscontraindicatedinpatientswithhypersensitivitytoDonepezilHydrochloride,piperidine

derivatives,ortoanyexcipientsusedintheformulation.(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:Cholinomimeticsarebelievedtohavesomepotentialtocause

generalisedconvulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

Theadministerationofdonepezilconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsorantagonistsof

thecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

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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.The

mortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumericallyhigher

thanintheplacebogroup(1.1%),however,thisdifferencewasnotstatisticallysignificant.Themajorityofdeathsin

patientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvariousvascularrelatedcauses,which

couldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.Ananalysisofallseriousnonfataland

fatalvasculareventsshowednodifferenceintherateofoccurrenceinthedonepezilhydrochloridegrouprelativeto

placebo.

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdoesnotinhibitthemetabolismoftheophylline,

warfarin,cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffected

byconcurrentadministrationofdigoxinorcimetidine.InvitrostudieshaveshownthatthecytochromeP450

isoenzymes3A4andtoaminorextent2D6areinvolvedinthemetabolismofdonepezil.Druginteractionstudies

performedinvitroshowthatketoconazoleandquinidine,inhibitorsofCYP3A4and2D6respectively,inhibit

donepezilmetabolism.ThereforetheseandotherCYP3A4inhibitors,suchasitraconazoleanderythromycin,and

CYP2D6inhibitors,suchasfluoxetinecouldinhibitthemetabolismofdonepezil.Inastudyinhealthyvolunteers,

ketoconazoleincreasedmeandonepezilconcentrationsbyabout30%.Enzymeinducers,suchasrifampicin,phenytoin,

carbamazepineandalcoholmayreducethelevelsofdonepezil.Sincethemagnitudeofaninhibitingorinducingeffect

isunknown,suchdrugcombinationsshouldbeusedwithcare.Donepezilhydrochloridehasthepotentialtointerfere

withmedicationshavinganticholinergicactivity.Thereisalsothepotentialforsynergisticactivitywithconcomitant

treatmentinvolvingmedicationssuchassuccinylcholine,otherneuro-muscularblockingagentsorcholinergicagonists

orbetablockingagentswhichhaveeffectsoncardiacconduction.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

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

potentialriskforhumansisunknown.

Donepezilshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

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4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreating

physicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplex

machines.

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

rare(1/10,000,<1/1,000).

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

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

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

**Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionordiscontinuationof

treatment.

***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

maybeusedasanantidotefordonepeziloverdosage.Intravenousatropinesulphatetitratedtoeffectisrecommended:

aninitialdoseof1.0to2.0mgintravenouslywithsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesin

bloodpressureandheartratehavebeenreportedwithothercholinomimeticswhenco-administeredwithquaternary

anticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/oritsmetabolitescanbe

Musculoskeletal,

connectivetissue

andbonedisorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

Generaldisorders

andadministration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

Serum

concentrationof

musclecreatine

kinase

Injury,poisoning

andprocedural

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-dementiadrugs,Anticholinesterases;ATCcode:N06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymewhichispresentmainlyoutsidethecentralnervoussystem.

Alzheimer'sDementia

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocytemembranes)

of63.6%and77.3%,respectivelywhenmeasuredpostdose.

Theinhibitionofacetylcholinesterase(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshownto

correlatetochangesinADAS-cog,asensitivescalewhichexaminesselectedaspectsofcognition.Thepotentialfor

donepezilhydrochloridetoalterthecourseoftheunderlyingneuropathologyhasnotbeenstudied.Thusdonepezil

cannotbeconsideredtohaveanyeffectontheprogressofthedisease.

Efficacyoftreatmentwithdonepezilhasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),the

ClinicianInterviewBasedImpressionofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivities

ofDailyLivingSubscaleoftheClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,home

andhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale.

*p<0.05

**p<0.01

Donepezilproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowerejudged

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

Donepezil5-mgGroup 18%* 18%*

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5.2Pharmacokineticproperties

Generalcharacteristics

Absorption:Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.

Plasmaconcentrationsandareaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeis

approximately70hours,thus,administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.

Approximatesteady-stateisachievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezil

hydrochlorideconcentrationsandtherelated

pharmacodynamicactivityshowlittlevariabilityoverthecourseoftheday.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution:Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaprotein

bindingoftheactivemetabolite6-O-desmethyldonepezilinnotknown.Thedistributionofdonepezilhydrochloridein

variousbodytissueshasnotbeendefinitivelystudied.

However,inamassbalancestudyconductedinhealthymalevolunteers,240hoursaftertheadministrationofasingle

5mgdoseof14C-labelleddonepezilhydrochloride,approximately28%ofthelabelremainedunrecovered.This

suggeststhatdonepezilhydrochlorideand/oritsmetabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion:Donepezilhydrochlorideisbothexcretedintheurineintactandmetabolizedbythecytochrome

P450systemtomultiplemetabolites,notallofwhichhavebeenidentified.

Followingadministrationofasingle5mgdoseof14C-labeleddonepezilhydrochloride,plasmaradioactivity,

expressedasapercentoftheadministereddose,waspresentprimarilyasintactdonepezilhydrochloride(30%),6-O-

desmethyldonepezil(11%-onlymetabolitethatexhibitsactivitysimilartodonepezilhydrochloride),donepezil-cis-N-

oxide(9%),5-O-desmethyldonepezil(7%)andtheglucuronideconjugateof5-O-desmethyldonepezil(3%).

Approximately57%ofthetotaladministeredradioactivitywasrecoveredfromtheurine(17%asunchanged

donepezil),and14.5%wasrecoveredfromthefaeces,suggestingbiotransformationandurinaryexcretionasthe

primaryroutesofelimination.Thereisnoevidencetosuggestenterohepaticrecirculationofdonepezilhydrochloride

and/oranyofitsmetabolites.

Plasmadonepezilconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsof

donepezilhydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjects

orinAlzheimer'spatientsorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwith

thoseofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteadystateconcentrations;meanAUCby

48%andmeanCmaxby39%(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

Lactosemonohydrate

Maizestarch

Hydroxypropylcellulose

Microcrystallinecellulose

Sodiumstarchglycolate-typeA

Magnesiumstearate

Coating

Opadry02B52480Yellowcontaining:

Hypromellose5cP(E464)

Titaniumdioxide(E171)

Macrogol400

Talc

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

BlisterpackofPVC/Aluminumfoilor

BlisterpackofPVC/PVdC/Al

Packsizes:

10mg:28,30,56,98,and100film-coatedtablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLtd

Spafield

CorkRoad

Cashel

Co.Tipperary

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8MARKETINGAUTHORISATIONNUMBER

PA408/77/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:13thNovember2009

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