DONELINN 5 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • DONELINN 5 MG FILM-COATED TABLETS
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DONELINN 5 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/020/001
  • Authorization date:
  • 11-09-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0915/020/001

CaseNo:2045697

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

HelsinnBirexTherapeuticsLtd

Damastown,Mulhuddart,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Donelinn5mgfilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom11/09/2009until10/09/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 24/09/2009 CRN 2045697 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Donelinn5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgofdonepezilhydrochloridehydrochloriderespectively.

Excipientsinclude:Lactose97.35mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet.

White,round,biconvexfilm-coatedtablets,7mmindiameterandmarkedDZ5ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DonelinntabletsareindicatedforthesymptomatictreatmentofmildormoderatedementiainAlzheimer'sdisease.

4.2Posologyandmethodofadministration

Adults/elderly

Theinitialdoseis5mgonceaday.Donelinnshouldbetakenorallyintheeveningjustpriortoretiring.The5mg/day

doseshouldbemaintainedforatleastonemonthinordertoassessthefirstclinicalresponsestothetreatmentand

obtainsteady-stateconcentrationofdonepezilhydrochloride.Followingtheonemonthclinicalassessmentoftreatment

at5mg/day,thedoseofDonelinncanbeincreasedto10mgonceaday.Themaximumrecommendeddailydoseis

10mg.Clinicalstudieswithdoseshigherthan10mg/dayhavenotbeenconducted.

TreatmentshallbeinitiatedandsupervisedbyadoctorexperiencedindiagnosingandtreatingdementiainAlzheimer's

disease.Diagnosesshallbeaccordingtoacceptedguidelines(e.g.DSMIV,ICD10).Donelinntreatmentshallonlybe

initiatedifarelativeoranothercaregiverisreadytomonitorregularlytheuseofthemedicinalproductforthepatient.

Maintenancetreatmentcanbecontinuedaslongasthepatientbenefitsfromit.ClinicalbenefitsofDonelinnuseshall

thereforeberevaluatedregularly.Discontinuationoftreatmentshouldbeconsideredwhenbenefitsarenolonger

observed.IndividualresponsetoDonelinncannotbepredicted.

UpondiscontinuationoftreatmentthebeneficialaffectsobservedduringDonelinnusearegraduallyreduced.Thereare

nosignsofareboundeffectfollowingabruptdiscontinuationoftreatment.

Renalandhepaticimpairment

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairmentasexcretionofdonepezilisnotaffectedby

suchimpairment.

Mildtomoderatehepaticimpairmentcanpossiblyincreaseexposure(seesection5.2),dosesshouldthereforebe

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Children

Donelinnisnotrecommendedforuseinchildren.

4.3Contraindications

Donelinniscontraindicatedinpatientswithknownhypersensitivitytodonepezilhydrochloride,piperidinederivatives,

ortoanyoftheexcipients.Donelinniscontraindicatedduringpregnancy,pleaserefertosection4.6ofSmPC.

4.4Specialwarningsandprecautionsforuse

UseofDonelinninpatientswithseveredementiainAlzheimer'sdisease,dementiacausedbyotherdiseasesormemory

loss(e.g.agerelateddementia)hasnotbeenstudied.

Anaesthesia:Donelinn,asacholinesteraseinhibitor,islikelytoexaggeratethemusclerelaxingeffectsof

succinylcholine-typeproductsduringanaesthesia.

Cardiovascularconditions:Pharmacologicalactionofcholinesteraseinhibitorsmayhavevasotoniceffectsonheart

rate(e.g.bradycardia).Thepossibilitiesofthiseffectmaybeparticularlyimportanttopatientswithsick-sinus

syndromeorothersupraventricularcardiacconductionconditions,i.e.sinoatrialblockandatrioventricularblock.Cases

ofsyncopeandseizureshavebeenreported.Whenexaminingsuchpatients,heartblockandlongsinusalpausesshould

beconsidered.

Gastro-intestinalconditions:Patientsatincreasedriskfordevelopingpepticulcers,e.g.thosewithahistoryofpeptic

ulcerorthosereceivingconcurrentnonsteroidalanti-inflammatorydrugs(NSAIDS)shouldbemonitoredforsymptoms

thereof.However,theclinicalstudieswithdonepezilshowednoincrease,relativetoplacebo,intheincidenceofeither

pepticulcersorgastrointestinalbleeding.

Genito-uritary:Althoughnotobservedinclinicaltrialsofdonepezilcholinomimeticsmaycauseurethralobstruction.

Neurologicalconditions:Seizures.Cholinomimeticsareconsideredhavingthepotentialtocausegeneralseizures.

SeizurescanhoweveralsobecausedbyAlzheimer'sdisease.

Cholinomimeticscanpossiblyworsenorincreaseextrapyramydalsymptoms.

Pulmonaryconditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

ConcomitantuseofDonelinnandotheracetylcholinesteraseinhibitorsoragentswhichinduceorinhibitthecholinergic

systemshouldbeavoided.

Severehepaticimpairment:Noinformationisavailablewithrespecttopatientswithseverehepaticimpairment.

Donelinncontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

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

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Themajorityofdeathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvarious

vascularrelatedcauses,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.An

analysisofallseriousnon-fatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthe

donepezilhydrochloridegrouprelativetoplacebo.

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

studiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroupsnumericallyexceededthat

inthedonepezilhydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oritsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,cimetidineor

digoxininhumans.Concurrentuseofdigoxinorcimetidinedoesnotaffectthemetabolismofdonepezilhydrochloride.

InvitrostudieshavedemonstratedthatcytochromeP450isoenzyme3A4andtosomeextent2D6,takepartinthe

metabolismofdonepezil.Interactionstudiesinvitrodemonstratethatketoconazole,aCYP3A4inhibitor,and

quinidine,aCYP2D6inhibitor,inhibitdonepezilmetabolism.

They,likeotherCYP3A4inhibitorssuchasitraconazoleanderythromycineandCYP2D6inhibitorssuchasfluoxetine

canthereforeinhibitdonepezilmetabolism.Inastudyinhealthyvolunteersketconazoleincreasedtheconcentrationof

donepezilabout30%.Enzymeinducers,suchasrifampicine,phenytoin,carbamazepinandalcohol,canreduceblood

concentrationofdonepezil.Cautionshouldbeexercisedduringconcurrentuseofthesemedicinalproductssincethe

extentoftheinhibitionorinductionisnotknown.Donepezilhydrochloridecanaffecttheefficacyofanticholinergic

products.Synergisticactivityisalsopossibleincaseofconcomitanttreatmentwithproductssuchassuccinylcholine,

otherneuro-muscularblockingagents,cholinergicagonistsorbeta-blockers,whichaffectcardiacconductivity.

4.6Pregnancyandlactation

Pregnancy

Studiesconductedinpregnantratsatdosesuptoapproximately80timesthehumandose,andinpregnantrabbitsat

dosesuptoapproximately50timesthehumandosedidnotdiscloseanyteratogeniceffects.However,inastudyin

whichpregnantratsweregivenapproximately50timesthehumandosefromday17ofgestationthroughday20

postpartum,therewasaslightincreaseinstillbirthsandaslightdecreaseinpupsurvivalthroughday4postpartum.No

sucheffectswereobservedatthenextlowerdosetested,approximately15timesthehumandose.

Thereisnoclinicalinformationavailableregardingtheuseofdonepezilinpregnantwomen.Donepezilshould

thereforenotbeusedduringpregnancy.

Lactation

Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreastmilkandnostudieshavebeencarriedout

inlactatingwomen.Womenusingdonepezilshouldthereforenotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines

Alzheimer'sdementiamayimpairthepatientsabilitytodriveorimpairtheirabilitytooperatemachinery.Additionally

donepezilmaycausefatigue,dizzinessandmusclespasms,particularlyatthebeginningoftreatmentorupondose

elevation.TheabilityofAlzheimer'spatientsusingdonepeziltocontinuedrivingandoperatingcomplicatedmachinery

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4.8Undesirableeffects

Themostcommonadverseeffectsarediarrhoea,musclespasms,fatigue,nausea,vomitingandsleepdisturbances.

Adverseeffectsreportedmoreoftenthaninisolatedcasesarelistedbelow,accordingtosystemorganclassand

frequency.Frequencyisdefinedas:common(>1/100,<1/10),uncommon(>1/1.000,<1/100),rare(>1/10.000,

<1/1.000),verycommon(>1/10),veryrare(<1/10.000)andnotknown(cannotbeestimatedfromavailabledata.

*Whenexaminingpatientswhohavesufferedfromseizuresorsyncope,heartblockandsinusalpausesshouldbe

considered(seesection4.4).

**Hallucinationshaveresolvedupondosereductionordiscontinuationoftreatment.

***Incaseofhepaticimpairmentfromanunknownsource,itshouldbeconsideredtostopusingDonelinn.

4.9Overdose

Theestimatedmeanlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreduced

spontaneousmovement,proneposition,staggeringgait,lacrimation,clonicconvulsions,depressedrespiration,

Systemorganclass Common Uncommon Rare

Infectionsand

infestations Cold

Metabolismandnutrition

disorders Anorexia

Psychiatricdisorders Hallucinations**

Agitation**

Aggression**

Nervoussystem

disorders Syncope*

Dizziness

Sleepdisturbances Seizures* Extrapyramidal

symptoms

Vasculardisorders Bradycardia Sinusandatriumblock

Atrioventricularblock

Gastrointestinal

disorders Diarrhoea(v.common)

Vomiting

Nausea(v.common)

Abdominalpain Gastrointestinalbleeding

Gastricandduodenal

ulcers

Hepatobilarydisorders Hepaticimpairment,

includinghepatitis***

Skinandsubcutaneous

tissuedisorders Rash

Pruritus

Musculoskeletaland

connectivetissue

disorders Musclespasms

Renalandurinary

disorders Incontinence

Generaldisordersand

administrationsite

conditions Headache(v.common)

Fatigue

Pain

Investigations Minorincreaseinserum

musclecreatininkinase

Injury,poisoningand

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Overdosewithcholinesteraseinhibitorscanresultincholinergiccrisischaracterizedbyseverenausea,vomiting,

salivation,sweating,bradycardia,hypotension,respiratorydepression,shockandconvulsions.Increasedmuscle

weaknessispossibleandmayresultindeathifrespiratorymusclesareinvolved.

Asineverycaseofoverdose,generalsupportivemeasuresshouldbeapplied.Tertiaryanticholinergicssuchasatropine

maybeusedasanantidoteforDonelinnoverdose.

Intravenousatropinesulphatetitratedtoeffectisrecommended:aninitialdoseof1.0to2.0mgIVwithsubsequent

dosesbaseduponclinicalresponse.Atypicalresponsesinbloodpressureandheartratehavebeenreportedwithother

cholinomimeticswhenco-administratedwithquaternaryanticholinergicssuchasglycopyrrolate.Itisnotknown

whetherdonepezilhydrochlorideand/oritsmetabolitescanberemovedbydialysis(haemodialysis,peritonealdialysis,

orhaemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterase;ATC-CodeN06DA02

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominatecholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethan

butyrylcholinesterase,anenzymewhichispresentmainlyoutsidethecentralnervoussystem.

AlzheimersDementia

InpatientswithAlzheimer'sdementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor

10mgofdonepezilhydrochlorideproducedsteady-stateinhibitionofacetylcholinesteraseactivityof63.3%and77.3%

respectivelywhenmeasuredpostdose(measuredinerythrocytemembranes).Correlationhasbeendemonstrated

betweenacetylcholineesterase(AChE)inhibitionofdonepezilhydrochlorideinredbloodcellsandchangesinADAS-

cog,ascalewhichexaminescognitivefunction.Theabilityofdonepezilhydrochloridetoaffecttheunderlying

neuropathogicaldevelopmenthasnotbeenstudied.ItcanthereforenotbeassumedthatDonelinncanaffectthe

progressionofthedisease.

Theresultsofdonepezilhydrochloridetreatmentwerestudiedinfourplacebocontrolledstudies,2lasted6monthsand

2lasted1year.

Inthe6monthsclinicaltrialanappraisalwasperformedattheendofthedonepeziltreatmentperiodusingthree

standardsforevaluationofefficacy:ADAS-Cog(tomeasurecognitiveability),ClinicalInterviewBasedImpressionof

ChangeswithCaregiverInput,withrespecttopossiblechangeswiththeassistanceofacloserelativeorcaregiver

(measuresgeneralability)andthenascaleforclinicalcognitivedeteriorationwithrespecttodailyactivities(evaluates

abilitytoparticipateinsocialinteractions,athome,inrecreationandwithrespecttoowncaretaking).

Thepatientswhometthefollowingcriteria,wereconsideredhavingrespondedtotreatment:

Response= ADAS-Cogimprovedbyatleast4points.

NoCIBICreduction(ClinicalInterviewBasedImpressionofChanges).

Nodeteriorationofdailyactivitiesbasedonmeasurementsofclinicalcognitiveability.

p<0,05

%response

Groupintendedtotreat

n=365 Groupsuccessfullyevaluated

n=352

Placebogroup 10% 10%

Donepezilhydrochloride5mggroup 18%* 18%*

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Donepezilhydrochloridedemonstratesadoserelatedstatisticallysignificantincreaseintheratioofpatientsconsidered

respondingtotreatment.

5.2Pharmacokineticproperties

Generalproperties:

Absorption

Peakplasmaconcentrationisreachedabout3-4hoursafteroraladministration.Plasmaconcentrationandareaunder

thecurve(AUC)increaseinproportionwiththedose.Terminaldispositionhalf-lifeisabout70hoursandfollowing

repeatedsingledailydosingsteadystateisachievedgradually.Steadystateisalmostreachedwithin3weeksfollowing

treatmentinitiation.Oncesteadystateisachieved,onlyminoralterationsindonepezilhydrochlorideplasmalevelsand

correspondingpharmacodynamicactivityareobservedoverthecourseoftheday.

Foodintakedoesnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution

Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Thebindingoftheactivemetabolite

6-O-desmethyldonepeziltoplasmaproteinsisnotknown.Thedistributionofdonepezilhydrochlorideinvariousbody

tissueshasnotbeendefinitivelystudied.

Howeverinastudyconductedinhealthymalevolunteers,approximately28%oftheadministereddoseremained

unaccountedfor,240hoursaftertheadministrationofasingle5mgdoseof 14

Clabelleddonepezilhydrochloride.This

indicatesthatdonepezilhydrochlorideand/oritsmetabolitesarepresentinthebodyformorethan10days.

Metabolism/excretion

DonepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochromeP450systemto

multiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mgdoseof 14

labelleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,wasmeasured

primarilyasintactdonepezilhydrochloride(30%),6-O-desmethyldonepezil(11%-theonlymetabolitethatexhibits

activitysimilartodonepezilhydrochloride),donepezil-cis-N-oxide(9%),5-O-desmethyldonepezil(7%)andthe

glucuronideconjugateof5-O-desmethyldonepezil(3%).Approximately57%ofthetotaladministeredradioactivity

wasrecoveredfromtheurine(17%asunchangeddonepezil),and14,5%wasrecoveredfromthefaeces,suggesting

metabolismandurinaryexcretionastheprimaryroutesofelimination.

Thereisnoevidencesuggestingentero-hepaticrecirculationofdonepezilhydrochlorideand/oranyofitsmetabolites.

Plasmahalf-lifeofdonepezilisabout70hours.

Sex,raceandsmokinghistoryhavenotclinicallysignificanteffectsonplasmalevelsofdonepezilhydrochloride.No

pharmacokineticstudieshavebeenperformedinhealthyelderlyindividualsorthosewithAlzheimer'sdisease.Mean

plasmalevelsarehoweveralmostthesameasinhealthyyoungvolunteers.

Steadystateconcentrationincreasedinpatientswithmildtomoderatehepaticimpairment,AUC48%ontheaverage

andC

39%ontheaverage(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthantheintended

pharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seesection4.9).Donepezilwasneither

mutagenicinbacterialnoranimalcells.Someclastogeniceffectswereobservedinvitrobutonlyatlevelsapproaching

thoseobviouslytoxicincellsandmorethan3.000timesthesteadystateplasmalevels.Noclastogeniceffectsorsigns

ofothergenotoxiceffectswereobservedinthemousemicronucleusmodelinvivo.Longtermcarcinogenicstudiesdid

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Donepezilhydrochloridedidnotaffectfertilityinratsandnoteratogeniceffectswereobservedinratsandrabbits.A

minorincreaseinstillbirthswashoweverobservedandlifeexpectancyofpupsslightlyreduced,whenthemedicinal

productwasbeenadministeredtopregnantratsat50timestherecommendeddosesforhumans(seesection4.6above).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Microcrystallinecellulose

Maizestarch

Magnesiumstearate

Polyvinylalcohol

Titaniumdioxide(E171)

Macrogol3350

Talc

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/aluminiumblisterfoil

HDPEbottlewithLDPEcap

Packsizes:

Foil:7,14,28,30,50,56,60,98,100,250tablets.

HDPEbottle:28,30,100,250tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexThereapeuticsLtd.

Damastown

Mulhuddart

Dublin15

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8MARKETINGAUTHORISATIONNUMBER

PA915/20/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11 th

September2009

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