GALTAM

Main information

  • Trade name:
  • GALTAM Film Coated Tablet 4 Milligram
  • Dosage:
  • 4 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GALTAM Film Coated Tablet 4 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/114/001
  • Authorization date:
  • 01-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0711/114/001

CaseNo:2025548

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Galtam4mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom01/02/2008until31/01/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Galtam4mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains4mgGalantamine(ashydrobromide).

Excipient:49.614mglactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Off-white,oval,biconvexfilm-coatedtabletsplainonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

GalantamineisindicatedforthesymptomatictreatmentofmildtomoderatelyseveredementiaoftheAlzheimertype.

4.2Posologyandmethodofadministration

Adults/Elderly

Administration

Galantamineshouldbeadministeredtwiceaday,preferablywithmorningandeveningmeals.Ensureadequatefluid

intakeduringtreatment(Seesection4.8).

Beforestartoftreatment

ThediagnosisofprobableAlzheimertypeofdementiashouldbeadequatelyconfirmedaccordingtocurrentclinical

guidelines(seesection4.4).

Startingdose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 2

Maintenancedose

Thetoleranceanddosingofgalantamineshouldbereassessedonaregularbasis,preferablywithinthreemonthsafter

startoftreatment.Thereafter,theclinicalbenefitofgalantamineandthepatient'stoleranceoftreatmentshouldbe

reassessedonaregularbasisaccordingtocurrentclinicalguidelines.Maintenancetreatmentcanbecontinuedforas

longastherapeuticbenefitisfavourableandthepatienttoleratestreatmentwithgalantamine.

Discontinuationofgalantamineshouldbeconsideredwhenevidenceofatherapeuticeffectisnolongerpresentorif

thepatientdoesnottoleratetreatment.

Theinitialmaintenancedoseis16mg/day(8mgtwiceaday)andpatientsshouldbemaintainedon16mg/dayforat

least4weeks.

Anincreasetothemaintenancedoseof24mg/day(12mgtwiceaday)shouldbeconsideredonanindividualbasis

afterappropriateassessmentincludingevaluationofclinicalbenefitandtolerability.

Inindividualpatientsnotshowinganincreasedresponseornottolerating24mg/day,adosereductionto16mg/day

shouldbeconsidered.

Thereisnoreboundeffectafterabruptdiscontinuationoftreatment(e.g.inpreparationforsurgery).

Children

Galantamineisnotrecommendedforuseinchildren.

Hepaticandrenalimpairment

Galantamineplasmalevelsmaybeincreasedinpatientswithmoderatetoseverehepaticorrenalimpairment.In

patientswithmoderatelyimpairedhepaticfunction,basedonpharmacokineticmodelling,itisrecommendedthat

dosingshouldbeginwith4mgoncedaily,preferablytakeninthemorning,foratleastoneweek.Thereafter,patients

shouldproceedwith4mgb.i.d.foratleast4weeks.Inthesepatients,dailydosesshouldnotexceed8mgb.i.d..In

patientswithseverehepaticimpairment(Child-Pughscoregreaterthan9),theuseofgalantamineiscontraindicated

(seesection4.3).Nodosageadjustmentisrequiredforpatientswithmildhepaticimpairment.

Forpatientswithacreatinineclearancegreaterthan9ml/minnodosageadjustmentisrequired.Inpatientswithsevere

renalimpairment(creatinineclearancelessthan9ml/min),theuseofgalantamineiscontraindicated(seesection4.3)

Concomitanttreatment

InpatientstreatedwithpotentCYP2D6orCYP3A4inhibitors(e.g.ketoconazole)dosereductionscanbeconsidered

(seesection4.5).

4.3Contraindications

Galantamineshouldnotbeadministeredtopatientswithaknownhypersensitivitytogalantaminehydrobromideorto

anyexcipientsusedintheformulations.Sincenodataareavailableontheuseofgalantamineinpatientswithsevere

hepatic(Child-Pughscoregreaterthan9)andsevererenal(creatinineclearancelessthan9ml/min)impairment,

galantamineiscontraindicatedinthesepopulations.Galantamineiscontra-indicatedinpatientswhohaveboth

significantrenalandhepaticdysfunction.

4.4Specialwarningsandprecautionsforuse

GalantamineisindicatedforapatientwithmildtomoderatelyseveredementiaofAlzheimertype.Thebenefitof

galantamineinpatientswithothertypesofdementiaorothertypesofmemoryimpairmenthasnotbeendemonstrated.

In2clinicaltrialsoftwoyearsdurationinindividualswithsocalledmildcognitiveimpairment(mildertypesof

memoryimpairmentnotfulfillingthecriteriaofAlzheimerdementia),galantaminetherapyfailedtodemonstrateany

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 3

Themortalityrateinthegalantaminegroupwassignificantlyhigherthanintheplacebogroup,14/1026(1.4%)patients

ongalantamineand3/1022(0.3%)patientsonplacebo.Thedeathswereduetovariouscauses.Abouthalfofthe

galantaminedeathsappearedtoresultfromvariousvascularcauses(myocardialinfarction,stroke,andsuddendeath).

TherelevanceofthisfindingforthetreatmentofpatientswithAlzheimerdementiaisunknown.InAlzheimer

dementia,placebo-controlledstudiesofonly6monthsdurationhavebeenconducted.Inthesestudiesnoincreased

mortalityinthegalantaminegroupsappeared.

AdiagnosisofAlzheimer'sdementiashouldbemadeaccordingtocurrentguidelinesbyanexperiencedphysician.

Therapywithgalantamineshouldoccurunderthesupervisionofaphysicianandshouldonlybeinitiatedifacaregiver

isavailablewhowillregularlymonitordrugintakebythepatient.

PatientswithAlzheimer'sdiseaseloseweight.Treatmentwithcholinesteraseinhibitors,includinggalantamine,has

beenassociatedwithweightlossinthesepatients.Duringtherapy,patient'sweightshouldbemonitored.

Aswithothercholinomimetics,galantamineshouldbegivenwithcautioninthefollowingconditions:

Cardiovascularconditions:becauseoftheirpharmacologicalaction,cholinomimeticsmayhavevagotoniceffectson

heartrate(e.g.bradycardia).Thepotentialforthisactionmaybeparticularlyimportanttopatientswith'sicksinus

syndrome'orothersupraventricularcardiacconductiondisturbancesorwhousedrugsthatsignificantlyreduceheart

rateconcomitantly,suchasdigoxinandbetablockersorforpatientswithanuncorrectedelectrolytedisturbance(e.g.

hyperkalaemia,hypokalaemia).

Cautionshouldthereforebeexercisedwhenadministeringgalantaminetopatientswithcardiovasculardiseases,e.g.

immediatepost-myocardialinfarctionperiod,new-onsetatrialfibrillation,seconddegreeheartblockorgreater,

unstableanginapectoris,orcongestiveheartfailure,especiallyNYHAgroupIII–IV.Inapooledanalysisofplacebo-

controlledstudiesinpatientswithAlzheimerdementiatreatedwithgalantamineanincreasedincidenceofcertain

cardiovascularadverseeventswereobserved(seesection4.8Undesirableeffects).

Gastrointestinalconditions:patientsatincreasedriskofdevelopingpepticulcers,e.g.thosewithahistoryofulcer

diseaseorthosepredisposedtotheseconditions,shouldbemonitoredforsymptoms.Theuseofgalantamineisnot

recommendedinpatientswithgastro-intestinalobstructionorrecoveringfromgastro-intestinalsurgery.

NeurologicalConditions:cholinomimeticsarebelievedtohavesomepotentialtocausegeneralisedconvulsions.

However,seizureactivitymayalsobeamanifestationofAlzheimer'sdisease.Inclinicaltrialstherewasnoincreasein

incidenceofconvulsionswithgalantaminecomparedwithplacebo.Inrarecasesanincreaseincholinergictonemay

worsenParkinsoniansymptoms.Inapooledanalysisofplacebo-controlledstudiesinpatientswithAlzheimer's

dementiatreatedwithgalantaminecerebrovasculareventswereuncommonlyobserved(seesection4.8Undesirable

effects).Thisshouldbeconsideredwhenadministeringgalantaminetopatientswithcerebrovasculardisease.

PulmonaryConditions:cholinomimeticsshouldbeprescribedwithcareforpatientswithahistoryofsevereasthmaor

obstructivepulmonarydiseaseoractivepulmonaryinfections(e.g.pneumonia).

Genitourinary:theuseofgalantamineisnotrecommendedinpatientswithurinaryoutflowobstructionorrecovering

frombladdersurgery.

Anaesthesia:galantamine,asacholinomimeticislikelytoexaggeratesuccinylcholinetypemusclerelaxationduring

anaesthesia.

SunsetyellowFCFaluminiumlake(E110),presentinthe12mgtablet,maycauseallergicreactions.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 4

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Becauseofitsmechanismofaction,galantamineshouldnotbegivenconcomitantlywithothercholinomimetics.

Galantamineantagonisestheeffectofanticholinergicmedication.Asexpectedwithcholinomimetics,a

pharmacodynamicinteractionispossiblewithdrugsthatsignificantlyreducetheheartrate(e.g.digoxinandbeta

blockers).Galantamine,asacholinomimetic,islikelytoexaggeratesuccinylcholine-typemusclerelaxationduring

anaesthesia.

Pharmacokineticinteractions

Multiplemetabolicpathwaysandrenalexcretionareinvolvedintheeliminationofgalantamine.

Concomitantadministrationwithfoodslowstheabsorptionrateofgalantaminebutdoesnotaffecttheextentof

absorption.Itisrecommendedthatgalantaminebetakenwithfoodinordertominimisecholinergicsideeffects.

Otherdrugsaffectingthemetabolismofgalantamine

Formaldruginteractionstudiesshowedanincreaseingalantaminebioavailabilityofabout40%duringco-

administrationofparoxetine(apotentCYP2D6inhibitor)andof30%and12%duringco-treatmentwithketoconazole

anderythromycin(bothCYP3A4inhibitors).Therefore,duringinitiationoftreatmentwithpotentinhibitorsof

CYP2D6(e.g.quinidine,paroxetine,fluoxetineorfluvoxamine)orCYP3A4(e.g.ketoconazole,ritonavir)patientsmay

experienceanincreasedincidenceofcholinergicsideeffects,predominantlynauseaandvomiting.Underthese

circumstances,basedontolerability,areductionofthegalantaminemaintenancedosecanbeconsidered(seesection

4.2).

Effectofgalantamineonthemetabolismofotherdrugs

Therapeuticdosesofgalantamine(12mgb.i.d.)hadnoeffectonthekineticsofdigoxinandwarfarin(seealso

pharmacodynamicinteractions).

4.6Pregnancyandlactation

Pregnancy

Forgalantaminenoclinicaldataonexposedpregnanciesareavailable.Animalstudiesindicateaslightlydelayed

developmentinfoetusesandneonates(seesection5.3).Cautionshouldbeexercisedwhenprescribingtopregnant

women.

Lactation

Itisnotknownwhethergalantamineisexcretedinhumanbreastmilkandtherearenostudiesinlactatingwomen.

Therefore,womenongalantamineshouldnotbreast-feed.

4.7Effectsonabilitytodriveandusemachines

Galantaminemaycausedizzinessandsomnolence,whichcouldaffecttheabilitytodriveorusemachines,especially

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 5

4.8Undesirableeffects

Themostcommonadverseeventsobservedinclinicaltrials(incidence > 5%andtwicethefrequencyofplacebo)were

nausea,vomiting,diarrhoea,abdominalpain,dyspepsia,anorexia,fatigue,dizziness,headache,somnolenceandweight

decrease.Nausea,vomitingandanorexiaweremorecommonlyobservedinwomen.

Othercommonadverseeventsobservedinclinicaltrials(incidence > 5%and > placebo)wereconfusion,depression,

fall,injury,insomnia,rhinitisandurinarytractinfection.

Themajorityoftheseadverseeventsoccurredduringthetitrationperiod.Nauseaandvomiting,themostfrequent

adverseevents,lastedlessthanaweekinmostcasesandthemajorityofpatientshadonlyoneepisode.Prescriptionof

anti-emeticsandensuringadequatefluidintakemaybeusefulintheseinstances.

Adverseeventsobservedduringclinicaltrialsandpostmarketingexperience.

Frequenciesaredefinedas:verycommon( > 1/10),common( > 1/100to<1/10),uncommon( > 1/1,000to<1/100),rare

( > 1/10,000to<1/1,000),veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata)

SystemOrganClass VeryCommon Common Uncommon Rare VeryRare

Infectionsand

infestations Rhinitis

Urinarytract

infections

Metabolismand

nutritiondisorders Anorexia

Weightdecrease Dehydration

(leadingtorenal

insufficiencyand

renalfailure)

Hypokalaemia

Psychiatricdisorders Confusion

Depression

(veryrarelywith

suicidality)

Insomnia Aggression

Agitation

Hallucinations

Nervous system

disorders Dizziness

Somnolence

Syncope

Tremor Paraesthesia Seizures Worseningof

Parkinsonism

labyrinth

disorders Tinnitus

Cardiacdisorders Atrial

arrhythmia

Myocardial

infarction

Myocardial

ischaemia

Palpitation Bradycardia

(severe) AVblock

Vasculardisorders Cerebrovascular

disease

Transient

ischaemicattack Hypotension

Gastrointestinal

disorders Vomiting

Nausea Abdominalpain

Diarrhoea

Dyspepsia Dysphagia

Gastrointestinal

bleeding

Skinandsubcutaneous

tissuedisorders Rash Increasedsweating

Musculoskeletaland

connectivetissue

disorders LegCramps

Generaldisordersand

administrationsite

conditions AstheniaFatigue

Fever

Headache

Malaise

Injury,poisoningand

procedural

complications Fall

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 6

Someoftheseadverseeventsmaybeattributabletocholinomimeticpropertiesofgalantamineorinsomecasesmay

representmanifestationsorexacerbationsoftheunderlyingdiseaseprocessescommonintheelderlypopulation.

4.9Overdose

Symptoms

Signsandsymptomsofsignificantoverdosingofgalantaminearepredictedtobesimilartothoseofoverdosingof

othercholinomimetics.Theseeffectsgenerallyinvolvethecentralnervoussystem,theparasympatheticnervous

system,andtheneuromuscularjunction.Inadditiontomuscleweaknessorfasciculations,someorallofthesignsofa

cholinergiccrisismaydevelop:severenausea,vomiting,gastro-intestinalcramping,salivation,lacrimation,urination,

defecation,sweating,bradycardia,hypotension,collapseandconvulsions.Increasingmuscleweaknesstogetherwith

trachealhypersecretionsandbronchospasm,mayleadtovitalairwaycompromise.

Inapost-marketingreport,bradycardia,QTprolongation,ventriculartachycardiaandtorsadesdepointesaccompanied

byabrieflossofconsciousnesswerereportedinassociationwithaninadvertentingestionofeight4mgtablets(32mg

total)onasingleday.

Treatment

Asinanycaseofoverdose,generalsupportivemeasuresshouldbeused.Inseverecases,anticholinergicssuchas

atropinecanbeusedasageneralantidoteforcholinomimetics.Aninitialdoseof0.5to1.0mgi.v.isrecommended,

withsubsequentdosesbasedontheclinicalresponse.

Becausestrategiesforthemanagementofoverdosearecontinuallyevolving,itisadvisabletocontactapoisoncontrol

centretodeterminethelatestrecommendationsforthemanagementofanoverdose.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidementiadrugs;ATC-code:N06DA04

Galantamine,atertiaryalkaloidisaselective,competitiveandreversibleinhibitorofacetylcholinesterase.Inaddition,

galantamineenhancestheintrinsicactionofacetylcholineonnicotinicreceptors,probablythroughbindingtoan

allostericsiteofthereceptor.Asaconsequence,anincreasedactivityinthecholinergicsystemassociatedwith

improvedcognitivefunctioncanbeachievedinpatientswithdementiaoftheAlzheimertype.

Clinicalstudies

Thedosagesofgalantamineeffectiveinplacebo-controlledclinicaltrialswithadurationof5to6monthswere16,24

and32mg/day.Ofthesedoses16and24mg/daywerejudgedtohavethebestbenefit/riskandwereretainedas

recommendedmaintenancedoses.Galantamine'sefficacyhasbeenshownusingoutcomemeasureswhichevaluatethe

threemajorsymptomcomplexesofthediseaseandaglobalscale:theADAS-Cog(aperformancebasedmeasureof

cognition),DADandADCS-ADL-Inventory(measurementsofbasicandinstrumentalActivitiesofDailyLiving),the

NeuropsychiatricInventory(ascalethatmeasuresbehaviouraldisturbances)andtheCIBIC-plus(aglobalassessment

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 7

Compositeresponderanalysisbasedonatleast4pointsimprovementinADAS-Cog/11comparedtobaseline

andCIBIC-plusunchanged+improved(1-4),andDAD/ADLscoreunchanged+improved.

5.2Pharmacokineticproperties

Galantamineisanalkaliniccompoundwithoneionisationconstant(pKa8.2).Itisslightlylipophilicandhasapartition

coefficient(LogP)betweenn-octanol/buffersolution(pH12)of1.09.Thesolubilityinwater(pH6)is31mg/ml.

Galantaminehasthreechiralcentres,theS,R,S-formisthenaturallyoccurringform.Galantamineispartially

metabolisedbyvariouscytochromes,mainlyCYP2D6andCYP3A4.Someofthemetabolitesformedduringthe

degradationofgalantaminehavebeenshowntobeactiveinvitrobutareofnoimportanceinvivo.

GENERALcharacteristicsofgalantamine

Absorption

Theabsorptionisrapid,withatmaxofabout1hourafterbothtabletsandoralsolution.Theabsolutebioavailabilityof

galantamineishigh,88.5±5.4%.ThepresenceoffooddelaystherateofabsorptionandreducesCmaxbyabout25%,

withoutaffectingtheextentofabsorption(AUC).

Distribution

Themeanvolumeofdistributionis175L.Plasmaproteinbindingislow,18%.

Metabolism

Upto75%ofgalantaminedosediseliminatedviametabolism.InvitrostudiesindicatethatCYP2D6isinvolvedinthe

formationofO-desmethylgalantamineandCYP3A4isinvolvedintheformationofN-oxide-galantamine.Thelevelsof

excretionoftotalradioactivityinurineandfaeceswerenotdifferentbetweenpoorandextensiveCYP2D6

metabolisers.Inplasmafrompoorandextensivemetabolisers,unchangedgalantamineanditsglucuronideaccounted

formostofthesampleradioactivity.Noneoftheactivemetabolitesofgalantamine(norgalantamine,O-

desmethylgalantamineandO-desmethyl-norgalantamine)couldbedetectedintheirunconjugatedforminplasmafrom

poorandextensivemetabolisersaftersingledosing.Norgalantaminewasdetectableinplasmafrompatientsafter

multipledosing,butdidnotrepresentmorethan10%ofthegalantaminelevels.Invitrostudiesindicatedthatthe

inhibitionpotentialofgalantaminewithrespecttothemajorformsofhumancytochromeP450isverylow.

Elimination

Galantamineplasmaconcentrationdeclinesbi-exponentially,withaterminalhalf-lifeintheorderof7-8hinhealthy

subjects.Typicaloralclearanceinthetargetpopulationisabout200mL/minwithintersubjectvariabilityof30%as

derivedfromthepopulationanalysis.Sevendaysafterasingleoraldoseof4mg³H-galantamine,90-97%ofthe

Atleast4pointsimprovementfrombaselineinADAS-Cog/11and

CIBIC-plusUnchanged+Improved

ChangeinDAD > 0

GAL-USA-1andGAL-INT-1(Month6) ChangeinADCS/ADL-Inventory > 0

GAL-USA-10(Month5)

Treatment N n(%)of

responder Comparison

withplacebo N n(%)of

responder Comparison

withplacebo

Diff(95%CI)

p-value † Diff(95%CI)

p-value †

ClassicalITT

Placebo 422 21(5.0) - - 273 18(6.6) - -

Gal16mg/day - - - - 266 39(14.7) 8.1(3,13) 0.003

Gal24mg/day 424 60(14.2) 9.2(5,13) <0.001 262 40(15.3) 8.7(3,14) 0.002

Trad.LOCF*

Placebo 412 23(5.6) - - 261 17(6.5) - -

Gal16mg/day - - - - 253 36(14.2) 7.7(2,13) 0.005

Gal24mg/day 399 58(14.5) 8.9(5,13) <0.001 253 40(15.8) 9.3(4,15) 0.001

CMHtestofdifferencefromplacebo.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 8

Afteri.v.infusionandoraladministration,18-22%ofthedosewasexcretedasunchangedgalantamineintheurinein

24hours,witharenalclearanceof68.4±22.0ml/min,whichrepresents20-25%ofthetotalplasmaclearance.

Dose-linearity

Afterrepeatedoraldosingof12and16mggalantamineb.i.d.,meantroughandpeakplasmaconcentrationsfluctuated

between29–97ng/mland42–137ng/ml.Thepharmacokineticsofgalantaminearelinearinthedoserangeof4-16

mgb.i.d.Inpatientstaking12or16mgb.i.d.,noaccumulationofgalantaminewasobservedbetweenmonths2and6.

Characteristicsinpatients

DatafromclinicaltrialsinpatientsindicatethattheplasmaconcentrationsofgalantamineinpatientswithAlzheimer's

diseaseare30-40%higherthaninhealthyyoungsubjects.Baseduponthepopulationpharmacokineticanalysis,

clearanceinfemalesubjectsis20%lowerascomparedtomales.Nomajoreffectsofageperseorracearefoundonthe

galantamineclearance.ThegalantamineclearanceinpoormetabolisersofCYP2D6isabout25%lowerthanin

extensivemetabolisers,butnobimodalityinthepopulationisobserved.Therefore,themetabolicstatusofthepatientis

notconsideredtobeofclinicalrelevanceintheoverallpopulation.

Thepharmacokineticsofgalantamineinsubjectswithmildhepaticimpairment(Child-Pughscoreof5-6)were

comparabletothoseinhealthysubjects.Inpatientswithmoderatehepaticimpairment(Child-Pughscoreof7-9),AUC

andhalf-lifeofgalantaminewereincreasedbyabout30%(seesection4.2).

Eliminationofgalantaminedecreaseswithdecreasingcreatinineclearanceasobservedinastudywithrenallyimpaired

subjects.ComparedtoAlzheimerpatients,peakandtroughplasmaconcentrationsarenotincreasedinpatientswitha

creatinineclearanceof>9ml/min.Therefore,noincreaseinadverseeventsisexpectedandnodosageadjustmentsare

needed(seesection4.2).

Pharmacokinetic/pharmacodynamicrelationship

Noapparentcorrelationbetweenaverageplasmaconcentrationsandefficacyparameters(i.e.ChangeinADAS-Cog11

andCIBIC-plusatMonth6)wereobservedinthelargePhaseIIItrialswithadose-regimenof12and16mgb.i.d.

Theseresultsindicatethatmaximaleffectsmaybeobtainedatthestudieddoses.

Plasmaconcentrationsinpatientsexperiencingsyncopewerewithinthesamerangeasintheotherpatientsatthesame

dose.

Theoccurrenceofnauseaisshowntocorrelatewithhigherpeakplasmaconcentrations(seesection4.5).

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansotherthanthoseexpectedfromthepharmacodynamiceffectof

galantamine.Thisassumptionisbasedonconventionalstudiesofsafetypharmacology,repeateddosetoxicity,

genotoxicityandcarcinogenicpotential.

Reproductiontoxicitystudiesshowedaslightdelayindevelopmentinratsandrabbits,atdoses,whicharebelowthe

thresholdoftoxicityinthepregnantfemales.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

LactoseMonohydrate

CitricacidMonohydrate

Talc

Magnesiumstearate

Silica,ColloidalAnhydrous

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 9

Film-coating:

Hypromellose

Titaniumdioxide(E171)

Lactosemonohydrate

Macrogol

Triacetin

IronOxideYellow(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

21months

6.4Specialprecautionsforstorage

Donotstoreabove30 °

6.5Natureandcontentsofcontainer

Alu/Alublister:10,56film-coatedtablets.

Highdensitypolyethylene(HDPE)containerwithpolypropylenelid:60film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork

8MARKETINGAUTHORISATIONNUMBER

PA0711/114/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

1stFebruary2008

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 06/03/2008 CRN 2025548 page number: 10