ARIPEZ 5 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
DONEPEZIL HYDROCHLORIDE
Available from:
Teva Pharma B.V.
INN (International Name):
DONEPEZIL HYDROCHLORIDE
Dosage:
5 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Authorised
Authorization number:
PA0749/034/001
Authorization date:
0000-00-00

PACKAGE LEAFLET: INFORMATION FOR THE USER

Aripez 5 mg Film coated Tablets

Aripez 10 mg Film coated Tablets

Donepezil hydrochloride

Read all of this leaflet carefully before you start taking this medicine.

-Keep this leaflet. You mayneed to read it again.

-If you have anyfurther questions, ask your doctor or pharmacist.

-This medicine has been prescribed for you. Do notpass it on to others. It mayharmthem, even if their

symptomsare the same as yours.

-If anyof the side effects gets serious, or if you notice anyside effects not listed in this leaflet, please tell

your doctor or pharmacist.

In this leaflet:

1.What Aripez is and what it is used for

2.Before you take Aripez

3.How to take Aripez

4.Possible side effects

5.How to store Aripez

6. Furtherinformation

1. WHAT ARIPEZ IS AND WHAT IT IS USED FOR

Donepezil belongs to a group of medicines called acetylcholine esterase inhibitors: it increases the levels of

the substance acetylcholine in the brain.

It is used to relieve the symptomsofmild to moderate Alzheimer’s dementia.

2. BEFORE YOU TAKE ARIPEZ

Remember:You must tell your doctor who your carers are.

Do not take Aripez

-if you are allergic (hypersensitive) to donepezil oranyof the other ingredients of Aripez Film-coated

Tablets.

-if you are allergic (hypersensitive) to other medicines containing apiperidine derivative(Aripez is a

piperidine derivative)

Take special care with Aripez

Treatment with Aripez should onlybe started and supervised bya doctor with experience in diagnosing and

treating Alzheimer’s dementia.

Informyour doctor if you:

-have ever had a stomach or intestinal ulcer

-frequentlytake pain-killers or treatment forrheumatism(pain or inflammation around bones, joints

or muscles): taking these medicines at the same time as Aripez could put you at greater risk of

developing stomach or intestinal ulcers.

-have ever had seizures

-have a heart condition

-have asthma or other long termlung disease

-have difficulties when urinating

-have ever had anyliver problems or hepatitis

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-are going to have an operation that requires you tohave a general anaesthetic. You must informthe

anaesthetist that you are taking Aripez .

The individual effect of Aripez cannot be predicted, therefore the effect of the treatment should be evaluated

regularlybya doctor.

Aripez is not recommended in children.

Taking other medicines

Informyour doctor if you are being treated with anyofthe following medicines, because the effect of Aripez

or the other medicine could be influencedif you take the two medicines together:

-Medicines against fungal infections,such as ketoconazole or itraconazole

-Antibiotics, such as erythromycin or rifampicin

-Heart medicines, such as quinidine or beta-blockers

-Medicines for epilepsy,such as phenytoin or carbamazepine

-Antidepressants, such as fluoxetine

- Muscle relaxants

- Other medicines that act the same wayas Aripez (such as galantamine or rivastigmine), and some

medicines for diarrhoea, Parkinson's disease or asthma.

Please tell your doctor or pharmacist if you are taking orhave recentlytaken anyother medicines, including

medicines obtained without a prescription.

Taking Aripez with food and drink

You must avoid drinking alcohol while you are being treated with Aripez , because it could reduce the effect

of Aripez .

Pregnancy and breast-feeding

You must not use Aripez if you are pregnant or breast-feeding.

Ask your doctor or pharmacist for advice before taking anymedicine.

Driving and using machines

Alzheimer's disease mayimpair your abilityto drive or operate machinery,and you must not performthese

activities unless your doctor tells you that it is safe to do so. Also, your medicine can cause tiredness,

dizziness and muscle cramp and if affected, you must not drive or operate machinery.

Important information about some of the ingredients of Aripez

Aripez Film-coated Tablets contain lactose. If youhave been told byyour doctor that you havean

intolerance to some sugars, contact your doctor before you take this medicinal product.

3. HOW TO TAKE ARIPEZ

Alwaystake Aripez exactlyas your doctor has told you. You should check with your doctor or pharmacist if

you are not sure. The usual dose is described below.

You must take Aripez bymouth once dailywith a glass of water in the evening just before bedtime.

The tablet strength you will take maychange depending on the length of time you have been taking the

medicine and on what your doctor will recommend. Usually, you will start bytaking 5 mg(one white tablet)

everynight. After one month, your doctor maytell youto take 10 mg(one yellow) tablet everynight. The

maximumrecommended dose is 10 mgeach night.

Both you and your caregivers should be aware of the doctor's instructions.

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If you take more Aripez than you should

Contact the doctor immediatelyif you take too high a dose of Aripez . At a high dose (overdose), the listed

side effects maybe worse (see section 4: Possible side effects). In particular, severe nausea, vomiting,

dribbling, sweating, a slow heart beat, low blood pressure, difficultybreathing, collapse, seizures and muscle

weakness mayoccur.

If you forget to take Aripez

If you forget to take a dose, take it as quicklyas possible after noticing this, unless it is time for the next

dose.

Do not take a double dose to make up for a forgotten dose.

If you have anyfurther questions on the use ofthis product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Aripez can cause side effects, although not everybodygets them.

Serious side effects:

You must tell your doctor immediatelyif you notice these serious side effects mentioned. You mayneed

urgent medical treatment.

-Fever with muscle stiffness, sweating or a lowered level of consciousness (a disorder called

"Neuroleptic Malignant Syndrome").

Common side effects (seen in more than 1 out of 100 and less than 1 out of 10 patients) are headache,

dizziness, sleeplessness, tiredness, fainting, hallucinations, unusual dreams including nightmares, agitation,

aggressive behaviour, pain, loss of appetite, digestive disturbances, including diarrhoea, nausea and

vomiting, incontinence, muscle cramps, rash, itching, , colds and accidents.

Uncommon side effects (seen in more than 1 out of 1,000 and less than 1 out of 100 patients) are seizures,

slow heart rate, bleeding in the digestive system,stomach and duodenal ulcer, and abnormal levels of the

substance creatine kinase in the blood.

Rare side effects (seen in more than 1 out of 10,000 and less than 1 out of 1,000 patients) are liver disorders

including hepatitis, heart problems like abnormal heart rate, as well as symptomssuch as shaking, stiffness

or uncontrollable movement of the face and tongue, but also of the limbs.

If hallucinations, agitation, aggressivebehaviour, convulsions or brief fainting episodes occur, you should

contact your doctor as the dose might need to be lowered or treatment stopped.

If anyof the side effects gets serious, or if you notice anyside effects not listed in this leaflet, please tell your

doctor or pharmacist.

5. HOW TO STORE ARIPEZ

Keep out of the reach and sight of children.

Do not use Aripez after the expirydate which is statedon the carton. The expirydate refers to the last dayof

that month.

This medicinal product does not require anyspecial storage conditions.

Medicines should not be disposed of via wastewateror household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

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6. FURTHER INFORMATION

What Aripez contains

The active substance is donepezil hydrochloride.

5 mg

Each tablet contains 5 mgdonepezil hydrochloride, equivalent to 4.56 mgdonepezil.

10 mg

Each tablet contains 10 mgdonepezil hydrochloride, equivalent to 9.12 mgdonepezil.

The other ingredients are: tablet core contains lactose,microcrystalline cellulose, pregelatinised maize starch,

hypromellose and magnesiumstearate. Thefilmcoating contains polyvinylalcohol, titaniumdioxide (E171),

macrogol, talc.

In addition the 10 mgtablets contain: iron oxide yellow (E172).

What Aripez looks like and contents of the pack

Aripez 5 mgtabletsare white filmcoated oval shaped tablets,debossed with "93" on one side and "7320" on

the other.

Aripez 10 mgtablets are yellow filmcoated oval shapedtablets, debossed with "93" on one side and "7321"

on the other.

The 5 mgtablets are available in pack sizes of 1, 7,14, 28, 30, 50, 56, 60, 84, 98 and 120 film-coated tablets.

Hospital pack: 50 (50 x 1) film-coated tablets. Calendar packs: 28, 56 and 98 film-coated tablets.

The 10 mgtablets are available in pack sizes of 1,7, 14, 28, 30, 50, 56, 60, 84, 98 and 120 film-coated

tablets. Hospital pack: 50 (50 x 1) film-coated tablets. Calendar pack: 28, 56, 98 film-coated tablets.

Not all pack sizes maybe marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Teva PharmaB.V.

Computerweg 10

3542 DR Utrecht

The Netherlands

Manufacturer:

TEVA UK Ltd

Brampton Road, Hampden Park,

Eastbourne, East Sussex, BN22 9AG

England

Pharmachemie B.V.

Swensweg 5, Postbus 552,

2003 RN Haarlem

The Netherlands

TEVA Santé SA

Rue Bellocier,

89107 Sens

France

TEVA Pharmaceutical Works Private Limited Company

Pallagi ùt 13,

4042 Debrecen

Hungary

TEVA Pharmaceutical Works Private Limited

Company

Táncsics Mihályút 82,

H-2100 Gödöllő,

Hungary Teva Czech Industries, s.r.o.

Ostravská 29,č.p. 305

47 70 Opava – Komárov

Czech Republic

4

This leaflet was last revised March 2013.

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aripez5mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgdonepezilhydrochloride,equivalentto4.56mgdonepezil.

Excipient:128.2mglactose/tablet

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Film-CoatedTablet.

WhiteFilm-Coatedovalshapedtablets,debossedwith"93"ononesideand"7320"ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AripeztabletsareindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer'sdementia.

4.2Posologyandmethodofadministration

Oraluse.

Adults/Elderly:

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

retiring.The5mg/daydoseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinicalresponses

totreatmenttobeassessedandtoallowsteady-stateconcentrationsofdonepezilhydrochloridetobeachieved.

Followingaone-monthclinicalassessmentoftreatmentat5mg/day,thedoseofdonepezilcanbeincreasedto10

mg/day(once-a-daydosing).Themaximumrecommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenot

beenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer's

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofDonepezilisseen.

Renalandhepaticimpairment:

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Childrenandadolescents:

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4.3Contraindications

Donepeziliscontraindicatedinpatientswithaknownhypersensitivitytodonepezilhydrochloride,piperidine

derivatives,ortoanyoftheexcipients(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:Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralised

convulsions.However,seizureactivitymayalsobeamanifestationofAlzheimer'sDisease.

Cholinomimeticsmayhavethepotentialtoexacerbateorinduceextrapyramidalsymptoms

PulmonaryConditions:Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwith

caretopatientswithahistoryofasthmaorobstructivepulmonarydisease.

Theadministerationofdonepezilconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsorantagonistsof

thecholinergicsystemshouldbeavoided.

SevereHepaticImpairment:Therearenodataforpatientswithseverehepaticimpairment.

Thismedicinalproductcontainslactose.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorbtionshouldnottakethismedicinalproduct.

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

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

dementiastudiesincludingthevasculardementiastudies(totaln=6888),themortalityrateintheplacebogroups

numericallyexceededthatinthedonepezilhydrochloridegroups.

NeurolepticMalignantSyndrome(NMS):

NMS,apotentiallylife-threateningconditioncharacterisedbyhyperthermia,musclerigidity,autonomicinstability,

alteredconsciousnessandelevatedserumcreatinephosphokinaselevels;additionalsignsmayincludemyoglobinuria

(rhadomyolysis)andacuterenalfailure.NMS,hasbeenreportedtooccurveryrarelyinassociationwithdonepezil,

particularlyinpatientsalsoreceivingconcomitantantipsychotics.Ifapatientdevelopssignsandsymptomsindicative

ofNMS,orpresentswithunexplainedhighfeverwithoutadditionalclinicalmanifestationsofNMS,treatmentshould

bediscontinued.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdoesnotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilhydrochlorideisnotaffectedbyconcurrent

administrationofdigoxinorcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthatketoconazoleandquinidine,inhibitors

ofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.ThereforetheseandotherCYP3A4inhibitors,suchas

itraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecouldinhibitthemetabolismofdonepezil.

Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezilconcentrationsbyabout30%.Enzyme

inducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil.Sincethe

magnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuro-muscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiac

conduction.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

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

potentialriskforhumansisunknown.

Donepezilshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilhydrochlorideisexcretedinhumanbreast

milkandtherearenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.Dementiamaycauseimpairment

ofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,donepezilcaninducefatigue,

dizzinessandmusclecramps,mainlywheninitiatingorincreasingthedose.Thetreatingphysicianshouldroutinely

evaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperatingcomplexmachines.

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

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*Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

SystemOrgan

Class Very

common Common Uncommon Rare Veryrare

Infectionsand

infestations Commoncold

Metabolismand

nutrition

disorders Anorexia

Psychiatric

disorders Hallucinations**

Agitation**

Aggressive

behaviour**

Abnormaldreams

andNightmares**

Nervoussystem

disorders Syncope*

Dizziness

Insomnia Seizure* Extrapyramidal

symptoms Neuroleptic

malignant

syndrome

Cardiacdisorders Bradycardia Sino-atrialblock

Atrioventricular

block

Gastrointestinal

disorders Diarrhoea

Nausea Vomiting

Abdominal

disturbance Gastrointestinal

haemorrhage

Gastricand

duodenalulcers

Hepato-biliary

disorders Liverdysfunction

including

hepatitis***

Skinand

subcutaneous

tissuedisorders Rash

Pruritis

Musculoskeletal,

connectivetissue

andbone

disorders Musclecramps

Renaland

urinarydisorders Urinary

incontinence

Generaldisorders

administration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

Injury,poisoning

andprocedural

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**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

removedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anticholinesterases

ATCcode:N06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymewhichispresentmainlyoutsidethecentralnervoussystem.

InpatientswithAlzheimer'sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredinerythrocytemembranes)

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

bloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesinADAS-cog,asensitivescalewhich

examinesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloridetoalterthecourseoftheunderlying

neuropathologyhasnotbeenstudied.Thusdonepezilcannotbeconsideredtohaveanyeffectontheprogressofthe

disease.

Efficacyoftreatmentwithdonepezilhasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points

NodeteriorationofCIBIC

NoDeteriorationofActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale.

%Response

IntenttoTreatPopulation

n=365 EvaluablePopulation

n=352

PlaceboGroup 10% 10%

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*p<0.05

**p<0.01

Donepezilproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswhowerejudged

treatmentresponders.

5.2Pharmacokineticproperties

Generalcharacteristics

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-labeleddonepezilhydrochloride,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.

Plasmadonepezilconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjectsorin

Alzheimer'spatientsorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreedwiththose

ofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteadystateconcentrations;meanAUCby

48%andmeanC

by39%(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seeSection4.9).Donepezilis

notmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffectswereobservedinvitroat

concentrationsovertlytoxictothecellsandmorethan3000timesthesteady-stateplasmaconcentrations.No

clastogenicorothergenotoxiceffectswereobservedinthemousemicronucleusmodelinvivo.Therewasnoevidence

Donepezil10-mgGroup 21%* 22%** Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/01/2014 CRN 2139716 page number: 6

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstillbirthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seeSection

4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core

Lactoseanhydrous

Microcrystallinecellulose

Pregelatinizedmaizestarch

Hypromellose

Magnesiumstearate

Coating

Polyvinylalcohol

Titaniumdioxide(E171)

Macrogol3350

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

TransparentPVC/PVdC–Aluminiumblister.

Packsizes:

1,7,14,28,30,50,56,60,84,98,and120film-coatedtablets.

Hospitalpacks:50(50x1)film-coatedtablets.

Calendarpacks:28,56and98film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/01/2014 CRN 2139716 page number: 7

8MARKETINGAUTHORISATIONNUMBER

PA0749/034/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1stFebruary2008

Dateoflastrenewal:28thOctober2012

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/01/2014 CRN 2139716 page number: 8

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