GALANTAMINE TEVA

Main information

  • Trade name:
  • GALANTAMINE TEVA
  • Dosage:
  • 8 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GALANTAMINE TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/022/002
  • Authorization date:
  • 19-12-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0749/022/002

CaseNo:2082897

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TevaPharmaB.V.

Computerweg10,3542DRUtrecht,Netherlands

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

GalantamineTeva8mgFilm-coatedTablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom01/09/2010until18/12/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 01/09/2010 CRN 2082897 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GalantamineTeva8mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains8mggalantamine(ashydrobromide)

Excipients:

Eachfilm-coatedtabletcontains51.747mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Pink,filmcoatedcapsuleshapedtablet,debossed"689"ononesideand"93"ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

GalantamineisindicatedforthesymptomatictreatmentofmildtomoderatelyseveredementiaoftheAlzheimertype.

4.2Posologyandmethodofadministration

Oraluse.

Adults/Elderly

Administration

Galantamineshouldbeadministeredtwiceaday,preferablywithmorningandeveningmeals.Thetabletsshouldbe

swallowedwholewithwaterandmustnotbebroken,crushedorchewed.Ensureadequatefluidintakeduringtreatment

(Seesection4.8).

Beforestartoftreatment

ThediagnosisofprobableAlzheimertypeofdementiashouldbeadequatelyconfirmedaccordingtocurrentclinical

guidelines(seesection4.4).

Startingdose

Therecommendedstartingdoseis8mg/day(4mgtwiceaday)forfourweeks.

Maintenancedose

Thetoleranceanddosingofgalantamineshouldbereassessedonaregularbasis,preferablywithinthreemonthsafter

startoftreatment.Thereafter,theclinicalbenefitofgalantamineandthepatient'stoleranceoftreatmentshouldbe

reassessedonaregularbasisaccordingtocurrentclinicalguidelines.Maintenancetreatmentcanbecontinuedforas

longastherapeuticbenefitisfavourableandthepatienttoleratestreatmentwithgalantamine.Discontinuationof

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toleratetreatment.

Theinitialmaintenancedoseis16mg/day(8mgtwiceaday)andpatientsshouldbemaintainedon16mg/dayforat

least4weeks.

Anincreasetothemaintenancedoseof24mg/day(12mgtwiceaday)shouldbeconsideredonanindividualbasis

afterappropriateassessmentincludingevaluationofclinicalbenefitandtolerability.

Inindividualpatientsnotshowinganincreasedresponseornottolerating24mg/day,adosereductionto16mg/day

shouldbeconsidered.

Thereisnoreboundeffectafterabruptdiscontinuationoftreatment(e.g.inpreparationforsurgery).

Children

Galantamineisnotrecommendedforuseinchildrenduetoalackofdataonsafetyandefficacy.

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

Hypersensitivitytogalantaminehydrobromideortoanyoftheexcipients.

Sincenodataareavailableontheuseofgalantamineinpatientswithseverehepatic(Child-Pughscoregreaterthan9)

andsevererenal(creatinineclearancelessthan9ml/min)impairment,galantamineiscontraindicatedinthese

populations.Galantamineiscontra-indicatedinpatientswhohavebothsignificantrenalandhepaticdysfunction.

4.4Specialwarningsandprecautionsforuse

GalantamineisindicatedforapatientwithmildtomoderatelyseveredementiaofAlzheimertype.Thebenefitof

galantamineinpatientswithothertypesofdementiaorothertypesofmemoryimpairmenthasnotbeendemonstrated.

In2clinicaltrialsoftwoyearsdurationinindividualswithsocalledmildcognitiveimpairment(mildertypesof

memoryimpairmentnotfulfillingthecriteriaofAlzheimerdementia),galantaminetherapyfailedtodemonstrateany

benefiteitherinslowingcognitivedeclineorreducingtheclinicalconversiontodementia.Themortalityrateinthe

galantaminegroupwassignificantlyhigherthanintheplacebogroup,14/1026(1.4%)patientsongalantamineand

3/1022(0.3%)patientsonplacebo.Thedeathswereduetovariouscauses.Abouthalfofthegalantaminedeaths

appearedtoresultfromvariousvascularcauses(myocardialinfarction,stroke,andsuddendeath).Therelevanceofthis

findingforthetreatmentofpatientswithAlzheimerdementiaisunknown.InAlzheimerdementia,placebo-controlled

studiesofonly6monthsdurationhavebeenconducted.Inthesestudiesnoincreasedmortalityinthegalantamine

groupsappeared.

AdiagnosisofAlzheimer'sdementiashouldbemadeaccordingtocurrentguidelinesbyanexperiencedphysician.

Therapywithgalantamineshouldoccurunderthesupervisionofaphysicianandshouldonlybeinitiatedifacaregiver

isavailablewhowillregularlymonitormedicinalproductintakebythepatient.

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beenassociatedwithweightlossinthesepatients.Duringtherapy,patient'sweightshouldbemonitored.

Aswithothercholinomimetics,galantamineshouldbegivenwithcautioninthefollowingconditions:

Cardiacdisorders

Becauseoftheirpharmacologicalaction,cholinomimeticsmayhavevagotoniceffectsonheartrate(e.g.bradycardia).

Thepotentialforthisactionmaybeparticularlyimportanttopatientswith'sicksinussyndrome'orother

supraventricularcardiacconductiondisturbancesorwhousemedicinalproductsthatsignificantlyreduceheartrate

concomitantly,suchasdigoxinandbetablockersorforpatientswithanuncorrectedelectrolytedisturbance(e.g.

hyperkalaemia,hypokalaemia).

Cautionshouldthereforebeexercisedwhenadministeringgalantaminetopatientswithcardiovasculardiseases,e.g.

immediatepost-myocardialinfarctionperiod,new-onsetatrialfibrillation,seconddegreeheartblockorgreater,

unstableanginapectoris,orcongestiveheartfailure,especiallyNYHAgroupIII–IV.

Inapooledanalysisofplacebo-controlledstudiesinpatientswithAlzheimerdementiatreatedwithgalantaminean

increasedincidenceofcertaincardiovascularadverseeventswereobserved(seesection4.8).

Gastrointestinaldisorders

Patientsatincreasedriskofdevelopingpepticulcers,e.g.thosewithahistoryofulcerdiseaseorthosepredisposedto

theseconditions,includingthosereceivingconcurrentnon-steroidalanti-inflammatorydrugs(NSAIDs),shouldbe

monitoredforsymptoms.Theuseofgalantamineisnotrecommendedinpatientswithgastro-intestinalobstructionor

recoveringfromgastro-intestinalsurgery.

Nervoussystemdisorders

Althoughcholinomimeticsarebelievedtohavesomepotentialtocauseseizures,seizureactivitymayalsobea

manifestationofAlzheimer'sdisease.Inclinicaltrialstherewasnoincreaseinincidenceofconvulsionswith

galantaminecomparedwithplacebo.InrarecasesanincreaseincholinergictonemayworsenParkinsoniansymptoms.

Inapooledanalysisofplacebo-controlledstudiesinpatientswithAlzheimer'sdementiatreatedwithgalantamine

cerebrovasculareventswereuncommonlyobserved(seesection4.8).Thisshouldbeconsideredwhenadministering

galantaminetopatientswithcerebrovasculardisease.

Respiratory,thoracicandmediastinaldisorders

Cholinomimeticsshouldbeprescribedwithcareforpatientswithahistoryofsevereasthmaorobstructivepulmonary

diseaseoractivepulmonaryinfections(e.g.pneumonia).

Renalandurinarydisorders

Theuseofgalantamineisnotrecommendedinpatientswithurinaryoutflowobstructionorrecoveringfrombladder

surgery.

Surgicalandmedicalprocedures

Galantamine,asacholinomimeticislikelytoexaggeratesuccinylcholinetypemusclerelaxationduringanaesthesia.

Other

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Becauseofitsmechanismofaction,galantamineshouldnotbegivenconcomitantlywithothercholinomimetics(such

asambenonium,donepezil,neostigmine,pyridostigmine,rivastigmineorsystemicallyadministeredpilocarpine).

Galantaminehasthepotentialtoantagonisetheeffectofanticholinergicmedication.Shouldanticholinergictreatment

suchasatropinebeabruptlystoppedthereisapotentialriskthatgalantamine'seffectcouldbeexacerbated.As

expectedwithcholinomimetics,apharmacodynamicinteractionispossiblewithmedicinalproductsthatsignificantly

reducetheheartratesuchasdigoxinandbetablockers,certaincalciumchannel-blockingagentsandamiodarone.

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ECGshouldbeconsidered.

Galantamine,asacholinomimetic,islikelytoexaggeratesuccinylcholine-typemusclerelaxationduringanaesthesia

especiallyincasesofpseudocholinesterasedeficiency

Pharmacokineticinteractions

Multiplemetabolicpathwaysandrenalexcretionareinvolvedintheeliminationofgalantamine.Thepossibilityof

clinicallyrelevantinteractionsislow.However,theoccurrenceofsignificantinteractionsmaybeclinicallyrelevantin

individualcases.

Concomitantadministrationwithfoodslowstheabsorptionrateofgalantaminebutdoesnotaffecttheextentof

absorption.Itisrecommendedthatgalantaminebetakenwithfoodinordertominimisecholinergicsideeffects.

Othermedicinalproductsaffectingthemetabolismofgalantamine

Formalinteractionstudiesshowedanincreaseingalantaminebioavailabilityofabout40%duringco-administrationof

paroxetine(apotentCYP2D6inhibitor)andof30%and12%duringco-treatmentwithketoconazoleanderythromycin

(bothCYP3A4inhibitors).Therefore,duringinitiationoftreatmentwithpotentinhibitorsofCYP2D6(e.g.quinidine,

paroxetine,fluoxetineorfluvoxamine)orCYP3A4(e.g.ketoconazoleorritonavir)patientsmayexperiencean

increasedincidenceofcholinergicsideeffects,predominantlynauseaandvomiting.Underthesecircumstances,based

ontolerability,areductionofthegalantaminemaintenancedosecanbeconsidered(seesection4.2).

Memantine,anN-methyl-D-aspartate(NMDA)receptorantagonist,atadoseof10mgonceadayfor2daysfollowed

by10mgtwiceadayfor12days,hadnoeffectonthepharmacokineticsofgalantamine(asprolonged-releasecapsules

16mgonceaday)atsteady-state.

Effectofgalantamineonthemetabolismofothermedicinalproducts

Therapeuticdosesofgalantamine(24mg/day)hadnoeffectonthekineticsofdigoxin,althoughpharmacodynamic

interactionsmayoccur(seealsopharmacodynamicinteractions).

Therapeuticdosesofgalantamine(24mg/day)hadnoeffectonthekineticsandprothrombintimeofwarfarin

4.6Pregnancyandlactation

Pregnancy:

Forgalantaminenoclinicaldataonexposedpregnanciesareavailable.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).Cautionshouldbeexercisedwhenprescribingtopregnantwomen.

Lactation:

Itisnotknownwhethergalantamineisexcretedinhumanbreastmilkandtherearenostudiesinlactatingwomen.

Therefore,womenongalantamineshouldnotbreast-feed.

4.7Effectsonabilitytodriveandusemachines

Galantaminehasminorormoderateinfluenceontheabilitytodriveandusemachines.Symptomsincludedizziness

andsomnolence,especiallyduringthefirstweeksafterinitiationoftreatment.

4.8Undesirableeffects

Themostcommonlyreportedadversereactionswerenauseaandvomiting.

Theyoccurredmainlyduringthetitrationperiod,lastedlessthanaweekinmostcasesandthemajorityofpatientshad

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Frequencyestimate:verycommon( ≥1/10),common(≥1/100to<1/10),uncommon(≥1/1,000to<1/100),rare(≥

1/10,000to<1/1,000)andveryrare(<1/10,000).

Adverseeventsobservedduringclinicaltrialsandpostmarketingexperience.

SystemOrgan

Class Very

Common Common Uncommon Rare VeryRare

Infectionsand

infestations Rhinitis

Urinarytract

infections

Metabolismand

nutrition

disorders Decreased

appetite

Anorexia Dehydration Hypokalaemia

Psychiatric

disorders HallucinationConfusion

Depression

(veryrarely

with

suicidality)

Insomnia Hallucination

visual

Hallucination

auditory Aggression

Agitation

Nervoussystem

disorders Syncope

Dizziness

Tremor

Headache

Somnolence

Lethargy Paraesthesia

Dysgeusia

Hypersomnia Worseningof

Parkinsonism

Seizures

Eyedisorders Visionblurred

Earand

labyrinth

disorders Tinnitus

Cardiac

disorders Bradycardia Supraventricular

extrasystoles

Atrioventricular

blockfirst

degree

Sinus

bradycardiaMyocardial

infarction

Myocardial

ischaemia

Palpitation

Vascular

disorders Hypertension Hypotension

Flushing

Cerebrovascular

disease

Transient

ischaemic

attack

Gastrointestinal

disorders Vomiting

Nausea Abdominal

pain

Abdominal

painupper

Diarrhoea

Dyspepsia

Stomach Retching Dysphagia

Gastrointestinal

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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.

Therehavebeenpost-marketingreportsoftorsadesdepointes,QTprolongation,bradycardia,ventriculartachycardia

andbrieflossofconsciousnessinassociationwithinadvertentoverdosesofgalantamine.Inonecasewherethedose

wasknown,eight4mgtablets(32mgtotal)wereingestedonasingleday.

Twoadditionalcasesofaccidentalingestionof32mg(nausea,vomitinganddrymouth;nausea,vomitingand

substernalchestpain)andoneof40mg(vomiting)resultedinbriefhospitalisationsforobservationwithfullrecovery.

Onepatient,whowasprescribed24mg/dayandhadahistoryofhallucinationsovertheprevioustwoyears,mistakenly

received24mgtwicedailyfor34daysanddevelopedhallucinationsrequiringhospitalisation.Anotherpatient,who

wasprescribed16mg/dayoforalsolution,inadvertentlyingested160mg(40ml)andexperiencedsweating,vomiting,

bradycardiaandnear-syncopeonehourlater,whichnecessitatedhospitaltreatment.Hissymptomsresolvedwithin24

hours.

Treatment

Asinanycaseofoverdose,generalsupportivemeasuresshouldbeused.Inseverecases,anticholinergicssuchas

atropinecanbeusedasageneralantidoteforcholinomimetics.Aninitialdoseof0.5to1.0mgintravenouslyis

recommended,withsubsequentdosesbasedontheclinicalresponse.

Becausestrategiesforthemanagementofoverdosearecontinuallyevolving,itisadvisabletocontactapoisoncontrol

discomfort

Abdominal

discomfort

Hepatobiliary

disorders Hepatitis

Skinand

subcutaneous

tissuedisorders Hyperhidrosis Rash

Musculoskeletal

andconnective

tissuedisorders Musclespasms Muscular

weakness

LegCramps

General

disordersand

administration

siteconditions Fatigue

AstheniaFever

Malaise

Investigations Weight

decreased Hepatic

enzyme

increased

Injury,

poisoningand

procedural

complications Fall

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anticholinesterases.

ATCcode:N06DA04

Galantamine,atertiaryalkaloidisaselective,competitiveandreversibleinhibitorofacetylcholinesterase.Inaddition,

galantamineenhancestheintrinsicactionofacetylcholineonnicotinicreceptors,probablythroughbindingtoan

allostericsiteofthereceptor.Asaconsequence,anincreasedactivityinthecholinergicsystemassociatedwith

improvedcognitivefunctioncanbeachievedinpatientswithdementiaoftheAlzheimertype.

Clinicalstudies

Thedosagesofgalantamineeffectiveinplacebo-controlledclinicaltrialswithadurationof5to6monthswere16,24

and32mg/day.Ofthesedoses16and24mg/daywerejudgedtohavethebestbenefit/riskandaretherecommended

maintenancedoses.Galantamine'sefficacyhasbeenshownusingoutcomemeasureswhichevaluatethethreemajor

symptomcomplexesofthediseaseandaglobalscale:theADAS-Cog/11(aperformancebasedmeasureofcognition),

DADandADCS-ADL-Inventory(measurementsofbasicandinstrumentalActivitiesofDailyLiving),the

NeuropsychiatricInventory(ascalethatmeasuresbehaviouraldisturbances)andtheCIBIC-plus(aglobalassessment

byanindependentphysicianbasedonaclinicalinterviewwiththepatientandcaregiver).

Compositeresponderanalysisbasedonatleast4pointsimprovementinADAS-Cog/11comparedtobaselineand

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

Treatment Atleast4pointsimprovementfrombaselineinADAS-Cog/11and

CIBIC-plusUnchanged+Improved

ChangeinDAD0

GAL-USA-1 and GAL-INT-1

(Month6) ChangeinADCS/ADL-Inventory

GAL-USA-10(Month5)

n(%)of

responder Comparison

withplacebo

n(%)of

responder Comparison

withplacebo

Diff(95%

p-value † Diff(95%

value †

ClassicalITT #

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

mg/day - - - - 266 39(14.7) 8.1 (3,

0.003

mg/day 424 60(14.2) 9.2 (5,

<0.001 262 40(15.3) 8.7 (3,

0.002

TraditionalLOCF*

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

mg/day - - - - 253 36(14.2) 7.7 (2,

0.005

mg/day 399 58(14.5) 8.9 (5,

<0.001 253 40(15.8) 9.3 (4,

0.001

ITT:IntentToTreat

CMHtestofdifferencefromplacebo.

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Theresultsofa26-weekdouble-blindplacebo-controlledtrial,inwhichpatientswithvasculardementiaandpatients

withAlzheimer'sdiseaseandconcomitantcerebrovasculardisease(“mixeddementia”)wereincluded,indicatethatthe

symptomaticeffectofgalantamineismaintainedinpatientswithAlzheimer'sdiseaseandconcomitantcerebrovascular

disease(seesection4.4,Nervoussystemdisorders).Inapost-hocsubgroupanalysis,nostatisticallysignificanteffect

wasobservedinthesubgroupofpatientswithvasculardementiaalone.

Inasecond26-weekplacebo-controlledtrialinpatientswithprobablevasculardementia,noclinicalbenefitof

galantaminetreatmentwasdemonstrated.

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,withat

ofabout1hourafterbothtabletsandoralsolution.Theabsolutebioavailabilityof

galantamineishigh,88.5±5.4%.ThepresenceoffooddelaystherateofabsorptionandreducesC

byabout25%,

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

radioactivityisrecoveredinurineand2.2–6.3%infaeces.Afterintravenousinfusionandoraladministration,18-22%

ofthedosewasexcretedasunchangedgalantamineintheurinein24hours,witharenalclearanceof68.4±22.0

ml/min,whichrepresents20-25%ofthetotalplasmaclearance.

Dose-linearity

Afterrepeatedoraldosingof12and16mggalantamineb.i.d.,meantroughandpeakplasmaconcentrationsfluctuated

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

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

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DatafromclinicaltrialsinpatientsindicatethattheplasmaconcentrationsofgalantamineinpatientswithAlzheimer's

diseaseare30-40%higherthaninhealthyyoungsubjects,primarilyduetotheadvancedageandreducedkidney

function.Baseduponthepopulationpharmacokineticanalysis,clearanceinfemalesubjectsis20%lowerascompared

tomales.Nomajoreffectsofageperseorracearefoundonthegalantamineclearance.Thegalantamineclearancein

poormetabolisersofCYP2D6isabout25%lowerthaninextensivemetabolisers,butnobimodalityinthepopulation

isobserved.Therefore,themetabolicstatusofthepatientisnotconsideredtobeofclinicalrelevanceintheoverall

population.

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

Microcrystallinecellulose

Crospovidone

Colloidalanhydroussilica

Magnesiumstearate

Coating:

Polyvinylalcohol

TitaniumDioxide(E171)

Macrogol4000

Talc

Ironoxideyellow(E172)

Ironoxidered(E172)

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

30months.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/PE/PVdC-Aluminiumblisters.

Blisterpacksof1,14,30,56,60,100&112film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaBV

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/22/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

December2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 01/09/2010 CRN 2082897 page number: 11