ARIZIME

Main information

  • Trade name:
  • ARIZIME Film Coated Tablet 10 Anhyd Milligrams
  • Dosage:
  • 10 Anhyd Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARIZIME Film Coated Tablet 10 Anhyd Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/036/002
  • Authorization date:
  • 28-05-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1063/036/002

CaseNo:2059594

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NicheGenericsLimited

1,TheCamCentre,WilburyWay,Hitchin,HertfordshireSG4OTW,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Arizime10mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/05/2010until27/05/2015.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arizime10mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains10mgdonepezilhydrochloride(asthemonohydrate),equivalentto9.12mgof

donepezil

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

Whiteoralmostwhite,round,biconvexfilm-coatedtabletsembossedwithstylized‘E382’ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ArizimeisindicatedforthesymptomatictreatmentofmildtomoderatelysevereAlzheimer’sdementia.

4.2Posologyandmethodofadministration

Adults/Elderly

Treatmentisinitiatedat5mgonceaday.Itshouldbetakenorallyintheevening,justpriortoretiring.The5mg/day

doseshouldbemaintainedforatleastonemonthinordertoallowtheearliestclinicalresponsestotreatmenttobe

assessedandtoallowsteady-stateconcentrationsofdonepeziltobeachieved.Followingaone-monthclinical

assessmentoftreatmentat5mg/day,thedoseofArizimecanbeincreasedto10mgonceaday.Themaximum

recommendeddailydoseis10mg.Dosesgreaterthan10mg/dayhavenotbeenstudiedinclinicaltrials.

TreatmentshouldbeinitiatedandsupervisedbyaphysicianexperiencedinthediagnosisandtreatmentofAlzheimer’s

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

shouldonlybestartedifacaregiverisavailablewhowillregularlymonitordrugintakeforthepatient.Maintenance

treatmentcanbecontinuedforaslongasatherapeuticbenefitforthepatientexists.Therefore,theclinicalbenefitof

donepezilshouldbereassessedonaregularbasis.Discontinuationshouldbeconsideredwhenevidenceofatherapeutic

effectisnolongerpresent.Individualresponsetodonepezilcannotbepredicted.

Upondiscontinuationoftreatment,agradualabatementofthebeneficialeffectsofArizimeisseen.Noreboundeffect

hasbeendetectedafteranabruptdiscontinuationofitsadministration.

Renalandhepaticimpairment

Asimilardoseschedulecanbefollowedforpatientswithrenalimpairment,asclearanceofdonepezilhydrochlorideis

notaffectedbythiscondition.

Duetopossibleincreasedexposureinmildtomoderatehepaticimpairment(seesection5.2),doseescalationshouldbe

performedaccordingtoindividualtolerability.Therearenodataforpatientswithseverehepaticimpairment.

Children

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 2

4.3Contraindications

Arizimeiscontraindicatedinpatientswithhypersensitivitytodonepezilhydrochloride,piperidinederivates,ortoany

oftheexcipients.

4.4Specialwarningsandprecautionsforuse

TheefficacyofdonepezilinpatientswithsevereAlzheimer’sdementia,othertypesofdementiaorothertypesof

memoryimpairment(e.g.age-relatedcognitivedecline),hasnotyetbeenestablished.

Anaesthesia

Arizimeasacholinesteraseinhibitorislikelytoexaggeratesuccinylcholine-typemusclerelaxationduringanaesthesia.

Cardiovascularconditions

Becauseoftheirpharmacologicalaction,cholinesteraseinhibitorsmayhavevagotoniceffectsonheartrate(e.g.,

bradycardia).Thepotentialforthisactionmaybeparticularlyimportanttopatientswith“sicksinussyndrome”orother

supraventricularcardiacconductionconditions,suchassinoatrialoratrioventricularblock.

Therehavebeenreportsofsyncopeandseizures.Ininvestigatingsuchpatientsthepossibilityofheartblockorlong

sinusalpausesshouldbeconsidered.

Gastrointestinalconditions

Patientsatincreasedriskfordevelopingulcers,e.g.,thosewithahistoryofulcerdiseaseorthosereceivingconcurrent

non-steroidalanti-inflammatorydrugs(NSAIDs),shouldbemonitoredforsymptoms.However,theclinicalstudies

withdonepezilshowednoincrease,relativetoplacebo,intheincidenceofeitherpepticulcerdiseaseorgastrointestinal

bleeding.

Genitourinary

Althoughnotobservedinclinicaltrialsofdonepezil,cholinomimeticsmaycausebladderoutflowobstruction.

Neurologicalconditions

Cholinomimeticsarebelievedtohavesomepotentialtocausegeneralizedconvulsions.However,seizureactivitymay

alsobeamanifestationofAlzheimer’sdisease.

Cholinomimeticsmayhaveapotentialtoexacerbateorinduceextrapyramidalsymptoms.

Pulmonaryconditions

Becauseoftheircholinomimeticactions,cholinesteraseinhibitorsshouldbeprescribedwithcaretopatientswitha

historyofasthmaorobstructivepulmonarydisease.

Theadministrationofdonepezilhydrochlorideconcomitantlywithotherinhibitorsofacetylcholinesterase,agonistsor

antagonistsofthecholinergicsystemshouldbeavoided.

Severehepaticimpairment

Therearenodataforpatientswithseverehepaticimpairment.

MortalityinVascularDementiaClinicalTrials

Threeclinicaltrialsof6monthsdurationwereconductedstudyingindividualsmeetingtheNINDS-AIRENcriteriafor

probableorpossiblevasculardementia(VaD).TheNINDS-AIRENcriteriaaredesignedtoidentifypatientswhose

dementiaappearstobeduesolelytovascularcausesandtoexcludepatientswithAlzheimer’sdisease.

Inthefirststudy,themortalityrateswere2/198(1%)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.

ThemortalityrateforthethreeVaDstudiescombinedinthedonepezilhydrochloridegroup(1.7%)wasnumerically

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 3

Themajorityofdeathsinpatientstakingeitherdonepezilhydrochlorideorplaceboappeartoresultfromvarious

vascularrelatedcauses,whichcouldbeexpectedinthiselderlypopulationwithunderlyingvasculardisease.An

analysisofallseriousnon-fatalandfatalvasculareventsshowednodifferenceintherateofoccurrenceinthe

donepezilhydrochloridegrouprelativetoplacebo.

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

dementiastudies(totaln=6888),themortalityrateintheplacebogroupsnumericallyexceededthatinthedonepezil

hydrochloridegroups.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Donepezilhydrochlorideand/oranyofitsmetabolitesdonotinhibitthemetabolismoftheophylline,warfarin,

cimetidineordigoxininhumans.Themetabolismofdonepezilisnotaffectedbyconcurrentadministrationofdigoxin

orcimetidine.

InvitrostudieshaveshownthatthecytochromeP450isoenzymes3A4andtoaminorextent2D6areinvolvedinthe

metabolismofdonepezil.Druginteractionstudiesperformedinvitroshowthatketoconazoleandquinidine,inhibitors

ofCYP3A4and2D6respectively,inhibitdonepezilmetabolism.ThereforetheseandotherCYP3A4inhibitors,suchas

itraconazoleanderythromycin,andCYP2D6inhibitors,suchasfluoxetinecouldinhibitthemetabolismofdonepezil.

Inastudyinhealthyvolunteers,ketoconazoleincreasedmeandonepezilconcentrationsbyabout30%.

Enzymeinducers,suchasrifampicin,phenytoin,carbamazepineandalcoholmayreducethelevelsofdonepezil.Since

themagnitudeofaninhibitingorinducingeffectisunknown,suchdrugcombinationsshouldbeusedwithcare.

Donepezilhydrochloridehasthepotentialtointerferewithmedicationshavinganticholinergicactivity.Thereisalso

thepotentialforsynergisticactivitywithconcomitanttreatmentinvolvingmedicationssuchassuccinylcholine,other

neuromuscularblockingagentsorcholinergicagonistsorbetablockingagentswhichhaveeffectsoncardiac

conduction.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofdonepezilinpregnantwomen.

Studiesinanimalshavenotshownteratogeniceffectbuthaveshownperi-andpostnataltoxicity(seesection5.3).The

potentialriskforhumansisunknown.

Arizimeshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Donepezilisexcretedinthemilkofrats.Itisnotknownwhetherdonepezilisexcretedinhumanbreastmilkandthere

arenostudiesinlactatingwomen.Therefore,womenondonepezilshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Donepezilhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Dementiamaycauseimpairmentofdrivingperformanceorcompromisetheabilitytousemachinery.Furthermore,

donepezilcaninducefatigue,dizzinessandmusclecramps,mainlywheninitiatingorincreasingdose.

Thetreatingphysicianshouldroutinelyevaluatetheabilityofpatientsondonepeziltocontinuedrivingoroperating

complexmachines.

4.8Undesirableeffects

Themostcommonadverseeventsarediarrhoea,musclecramps,fatigue,nausea,vomitingandinsomnia.Dizziness,

headaches,pain,accidentsandthecommoncoldhavealsobeenreported.Inmostcasesthesegoawaywithouthaving

tostoptreatment.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 4

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)andnotknown(cannotbeestimatedfromavailabledata).

Ininvestigatingpatientsforsyncopeorseizurethepossibilityofheartblockorlongsinusalpausesshouldbe

considered(seesection4.4)

Reportsofhallucinations,agitationandaggressivebehaviourhaveresolvedondose-reductionor

discontinuationoftreatment.

Systemorganclass Very

common 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-atrial

block

Atrioventricular

block

Gastrointestinal

disorders Diarrhoea

Nausea Vomiting

Abdominal

disturbance Gastrointestinal

haemorrhage

Gastricand

duodenalulcers

Hepatobiliary

disorders Liver

dysfunction

including

hepatitis***

Skinand

subcutaneoustissue

disorders Rash

Pruritus

Musculoskeletal

andconnective

tissuedisorders Musclecramps

Renalandurinary

disorders Urinary

incontinence

Generaldisorders

andadministration

siteconditions Headache Fatigue

Pain

Investigations Minorincreasein

serum

concentrationof

musclecreatine

kinase

Injury,poisoning

andprocedural

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 5

4.9Overdose

Theestimatedmedianlethaldoseofdonepezilhydrochloridefollowingadministrationofasingleoraldoseinmiceand

ratsis45and32mg/kg,respectively,orapproximately225and160timesthemaximumrecommendedhumandoseof

10mgperday.Dose-relatedsignsofcholinergicstimulationwereobservedinanimalsandincludedreduced

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

salivation,miosis,fasciculationandlowerbodysurfacetemperature.

Overdosewithcholinesteraseinhibitorscanresultincholinergiccrisischaracterizedbyseverenausea,vomiting,

salivation,sweating,bradycardia,hypotension,respiratorydepression,collapseandconvulsions.Increasingmuscle

weaknessisapossibilityandmayresultindeathifrespiratorymusclesareinvolved.

Asinanycaseofoverdose,generalsupportivemeasuresshouldbeutilised.Tertiaryanticholinergicssuchasatropine

maybeusedasanantidoteforArizimeoverdosage.Intravenousatropinesulphatetitratedtoeffectisrecommended:an

initialdoseof1mgto2mgiv.withsubsequentdosesbaseduponclinicalresponse.Atypicalresponsesinblood

pressureandheartratehavebeenreportedwithothercholinomimeticswhencoadministeredwithquaternary

anticholinergicssuchasglycopyrrolate.Itisnotknownwhetherdonepezilhydrochlorideand/oritsmetabolitescanbe

removedbydialysis(hemodialysis,peritonealdialysis,orhemofiltration).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-dementiadrugs;anticholinesterase;ATCcodeN06DA02.

Donepezilhydrochlorideisaspecificandreversibleinhibitorofacetylcholinesterase,thepredominantcholinesterasein

thebrain.Donepezilhydrochlorideisinvitroover1000timesmorepotentaninhibitorofthisenzymethanof

butyrylcholinesterase,anenzymethatispresentmainlyoutsidethecentralnervoussystem.

InpatientswithAlzheimer’sDementiaparticipatinginclinicaltrials,administrationofsingledailydosesof5mgor10

mgofdonepezilhydrochlorideproducedsteady-stateinhibitionofacetylcholinesteraseactivity(measuredin

erythrocytemembranes)of63.6%and77.3%,respectivelywhenmeasuredpostdose.Theinhibitionof

acetylcholinesterase(AChE)inredbloodcellsbydonepezilhydrochloridehasbeenshowntocorrelatetochangesin

ADAS-cog,asensitivescalewhichexaminesselectedaspectsofcognition.Thepotentialfordonepezilhydrochloride

toalterthecourseoftheunderlyingneuropathologyhasnotbeenstudied.Thusdonepezilhydrochloridecannotbe

consideredtohaveanyeffectontheprogressofthedisease.

Efficacyoftreatmentwithdonepezilhasbeeninvestigatedinfourplacebo-controlledtrials,2trialsof6-monthduration

and2trialsof1-yearduration.

Inthe6monthsclinicaltrial,ananalysiswasdoneattheconclusionofdonepeziltreatmentusingacombinationof

threeefficacycriteria:theADAS-Cog(ameasureofcognitiveperformance),theClinicianInterviewBasedImpression

ofChangewithCaregiverInput(ameasureofglobalfunction)andtheActivitiesofDailyLivingSubscaleofthe

ClinicalDementiaRatingScale(ameasureofcapabilitiesincommunityaffairs,homeandhobbiesandpersonalcare).

Patientswhofulfilledthecriterialistedbelowwereconsideredtreatmentresponders.

Response=ImprovementofADAS-Cogofatleast4points,andnodeteriorationofCIBIC,andnodeteriorationof

ActivitiesofDailyLivingSubscaleoftheClinicalDementiaRatingScale.

*p<0.05

**p<0.01 %Response

Intenttotreatpopulation

n=365 Evaluablepopulation

n=352

Placebogroup 10% 10%

DonepezilHCl5mg-Group 18%* 18%*

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 6

Donepezilhydrochlorideproducedadose-dependentstatisticallysignificantincreaseinthepercentageofpatientswho

werejudgedtreatmentresponders.

5.2Pharmacokineticproperties

Absorption

Maximumplasmalevelsarereachedapproximately3to4hoursafteroraladministration.Plasmaconcentrationsand

areaunderthecurveriseinproportiontothedose.Theterminaldispositionhalf-lifeisapproximately70hours.

Administrationofmultiplesingle-dailydosesresultsingradualapproachtosteady-state.Approximatesteady-stateis

achievedwithin3weeksafterinitiationoftherapy.Onceatsteady-state,plasmadonepezilhydrochloride

concentrationsandtherelatedpharmacodynamicactivityshowlittlevariabilityoverthecourseoftheday.

Fooddidnotaffecttheabsorptionofdonepezilhydrochloride.

Distribution

Donepezilhydrochlorideisapproximately95%boundtohumanplasmaproteins.Theplasmaproteinbindingofthe

activemetabolite6-O-desmethyldonepezilisnotknown.Thedistributionofdonepezilhydrochlorideinvariousbody

tissueshasnotbeendefinitivelystudied.Inhealthymalevolunteers,240hoursaftertheadministrationofasingle5mg

doseof 14

C-labelleddonepezilhydrochloride,approximately28%ofthelabelremainedunrecovered.Thissuggests

thatdonepezilhydrochlorideand/oritsmetabolitesmaypersistinthebodyformorethan10days.

Metabolism/Excretion

DonepezilhydrochlorideisbothexcretedintheurineintactandmetabolisedbythecytochromeP450systemto

multiplemetabolites,notallofwhichhavebeenidentified.Followingadministrationofasingle5mgdoseof 14

labelleddonepezilhydrochloride,plasmaradioactivity,expressedasapercentoftheadministereddose,waspresent

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

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

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

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

biotransformationandurinaryexcretionastheprimaryroutesofelimination.Thereisnoevidencetosuggest

enterohepaticrecirculationofdonepezilhydrochlorideand/oranyofitsmetabolites.

Plasmadonepezilconcentrationsdeclinewithahalf-lifeofapproximately70hours.

Sex,raceandsmokinghistoryhavenoclinicallysignificantinfluenceonplasmaconcentrationsofdonepezil

hydrochloride.Thepharmacokineticsofdonepezilhasnotbeenformallystudiedinhealthyelderlysubjectsorin

Alzheimer’sdementiapatientsorvasculardementiapatients.Howevermeanplasmalevelsinpatientscloselyagreed

withthoseofyounghealthyvolunteers.

Patientswithmildtomoderatehepaticimpairmenthadincreaseddonepezilsteady-stateconcentrations;meanAUCby

48%andmeanC

by39%(seesection4.2).

5.3Preclinicalsafetydata

Extensivetestinginexperimentalanimalshasdemonstratedthatthiscompoundcausesfeweffectsotherthanthe

intendedpharmacologicaleffectsconsistentwithitsactionasacholinergicstimulator(seesection4.9).Donepezilis

notmutagenicinbacterialandmammaliancellmutationassays.Someclastogeniceffectswereobservedinvitroat

concentrationsovertlytoxictothecellsandmorethan3000timesthesteady-stateplasmaconcentrations.No

clastogenicorothergenotoxiceffectswereobservedinthemousemicronucleusmodel invivo .Therewasnoevidence

ofoncogenicpotentialinlongtermcarcinogenicitystudiesineitherratsormice.

Donepezilhydrochloridehadnoeffectonfertilityinrats,andwasnotteratogenicinratsorrabbits,buthadaslight

effectonstillbirthsandearlypupsurvivalwhenadministeredtopregnantratsat50timesthehumandose(seesection

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 7

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Microcrystallinecellulose

Hydroxypropylcellulose

Magnesiumstearate

Film-coating:

OpadryY-1-7000White:hypromellose,titaniumdioxide(E171)andmacrogol400.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

28or56film-coatedtabletsaresuppliedinOPA/Al/PVC//AlufoilorinPVC/PVdC//Alufoilblisterincartonbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

HertfordshireSG4OTW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/36/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28 th

May2010

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 01/06/2010 CRN 2059594 page number: 8