GABAPENTIN 800 MG FILM COATED TABLETS

Main information

  • Trade name:
  • GABAPENTIN 800 MG FILM COATED TABLETS
  • Dosage:
  • 800 Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GABAPENTIN 800 MG FILM COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1300/001/002
  • Authorization date:
  • 10-03-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PA1300/001/002

CaseNo:2036728

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

WinthropArzneimittelGmbH

Industriestrasse26,56218Mulheim-Karlich,Germany

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gabapentin800mgFilmCoatedTablets800MilligramCoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom09/05/2007until.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gabapentin800mgFilmCoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each800mgfilm-coatedtabletcontains800mgofgabapentin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

White,biconvexovalshaped,filmcoatedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Gabapentinisindicatedasadjunctivetherapyinthetreatmentofpartialseizureswithandwithoutsecondary

generalizationinadultsandchildrenaged6yearsandabove(seesection5.1).

Gabapentinisindicatedasmonotherapyinthetreatmentofpartialseizureswithandwithoutsecondarygeneralization

inadultsandadolescentsaged12yearsandabove.

Treatmentofperipheralneuropathicpain

Gabapentinisindicatedforthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-

herpeticneuralgiainadults.

4.2Posologyandmethodofadministration

Fororaluse.

Gabapentincanbegivenwithorwithoutfoodandshouldbeswallowedwholewithsufficientfluidintake(e.g.aglass

ofwater).

ForallindicationsatitrationschemefortheinitiationoftherapyisdescribedinTable1,whichisrecommendedfor

adultsandadolescentsaged12yearsandabove.Dosinginstructionsforchildrenunder12yearsofageareprovided

underaseparatesub-headinglaterinthissection.

Table1

DOSINGCHART–INITIALTITRATION

Day1 Day2 Day3

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Epilepsy

Epilepsytypicallyrequireslong-termtherapy.Dosageisdeterminedbythetreatingphysicianaccordingtoindividual

toleranceandefficacy.Wheninthejudgmentoftheclinicianthereisaneedfordosereduction,discontinuation,or

substitutionwithanalternativemedication,thisshouldbedonegraduallyoveraminimumofoneweek.

Adultsandadolescents:

Inclinicaltrials,theeffectivedosingrangewas900to3600mg/day.Therapymaybeinitiatedbytitratingthedoseas

describedinTable1orbyadministering300mgthreetimesaday(TID)onDay1.Thereafter,basedonindividual

patientresponseandtolerability,thedosecanbefurtherincreasedin300mg/dayincrementsevery2-3daysuptoa

maximumdoseof3600mg/day.Slowertitrationofgabapentindosagemaybeappropriateforindividualpatients.The

minimumtimetoreachadoseof1800mg/dayisoneweek,toreach2400mg/dayisatotalof2weeks,andtoreach

3600mg/dayisatotalof3weeks.Dosagesupto4800mg/dayhavebeenwelltoleratedinlong-termopen-label

clinicalstudies.Thetotaldailydoseshouldbedividedinthreesingledoses,themaximumtimeintervalbetweenthe

dosesshouldnotexceed12hourstopreventbreakthroughconvulsions.

Childrenaged6yearsandabove:

Thestartingdoseshouldrangefrom10to15mg/kg/dayandtheeffectivedoseisreachedbyupwardtitrationovera

periodofapproximatelythreedays.Theeffectivedoseofgabapentininchildrenaged6yearsandolderis25to35

mg/kg/day.Dosagesupto50mg/kg/dayhavebeenwelltoleratedinalongtermclinicalstudy.Thetotaldailydose

shouldbedividedinthreesingledoses,themaximumtimeintervalbetweendosesshouldnotexceed12hours.

Itisnotnecessarytomonitorgabapentinplasmaconcentrationstooptimizegabapentintherapy.Further,gabapentin

maybeusedincombinationwithotherantiepilepticmedicinalproductswithoutconcernforalterationoftheplasma

concentrationsofgabapentinorserumconcentrationsofotherantiepilepticmedicinalproducts.

Peripheralneuropathicpain

Adults:

ThetherapymaybeinitiatedbytitratingthedoseasdescribedinTable1.Alternatively,thestartingdoseis900mg/day

givenasthreeequallydivideddoses.Thereafter,basedonindividualpatientresponseandtolerability,thedosecanbe

furtherincreasedin300mg/dayincrementsevery2-3daysuptoamaximumdoseof3600mg/day.Slowertitrationof

gabapentindosagemaybeappropriateforindividualpatients.Theminimumtimetoreachadoseof1800mg/dayis

oneweek,toreach2400mg/dayisatotalof2weeks,andtoreach3600mg/dayisatotalof3weeks.

Inthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-herpeticneuralgia,efficacy

andsafetyhavenotbeenexaminedinclinicalstudiesfortreatmentperiodslongerthan5months.Ifapatientrequires

dosinglongerthan5monthsforthetreatmentofperipheralneuropathicpain,thetreatingphysicianshouldassessthe

patient’sclinicalstatusanddeterminetheneedforadditionaltherapy.

Instructionforallareasofindication

Inpatientswithpoorgeneralhealth,i.e.,lowbodyweight,afterorgantransplantationetc.,thedoseshouldbetitrated

moreslowly,eitherbyusingsmallerdosagestrengthsorlongerintervalsbetweendosageincreases.

Useinelderlypatients(over65yearsofage)

Elderlypatientsmayrequiredosageadjustmentbecauseofdecliningrenalfunctionwithage(seeTable2).

Somnolence,peripheraloedemaandastheniamaybemorefrequentinelderlypatients.

Useinpatientswithrenalimpairment

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undergoinghaemodialysis.Gabapentin100mgcapsulescanbeusedtofollowdosingrecommendationsforpatients

withrenalinsufficiency.

Totaldailydoseshouldbeadministeredasthreedivideddoses.Reduceddosagesareforpatientswith

renalimpairment(creatinineclearance<79ml/min).

Tobeadministeredas300mgeveryotherday.

Forpatientswithcreatinineclearance<15ml/min,thedailydoseshouldbereducedinproportionto

creatinineclearance(e.g.patientswithacreatinineclearanceof7.5ml/minshouldreceiveone-halfthe

dailydosethatpatientswithacreatinineclearanceof15ml/minreceive).

Useinpatientsundergoinghaemodialysis

Foranuricpatientsundergoinghaemodialysiswhohaveneverreceivedgabapentin,aloadingdoseof300to400mg,

then200to300mgofgabapentinfollowingeach4hoursofhaemodialysis,isrecommended.Ondialysis-freedays,

thereshouldbenotreatmentwithgabapentin.Forrenallyimpairedpatientsundergoinghaemodialysis,themaintenance

doseofgabapentinshouldbebasedonthedosingrecommendationsfoundinTable2.Inadditiontothemaintenance

dose,anadditional200to300mgdosefollowingeach4-hourhaemodialysistreatmentisrecommended.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Ifapatientdevelopsacutepancreatitisundertreatmentwithgabapentin,discontinuationofgabapentinshouldbe

considered(seesection4.8).

Althoughthereisnoevidenceofreboundseizureswithgabapentin,abruptwithdrawalofanticonvulsantsinepileptic

patientsmayprecipitatestatusepilepticus(seesection4.2).

Aswithotherantiepilepticmedicinalproducts,somepatientsmayexperienceanincreaseinseizurefrequencyorthe

onsetofnewtypesofseizureswithgabapentin.

Aswithotheranti-epileptics,attemptstowithdrawconcomitantanti-epilepticsintreatmentrefractorypatientsonmore

thanoneanti-epileptic,inordertoreachgabapentinmonotherapyhavealowsuccessrate.

Gabapentinisnotconsideredeffectiveagainstprimarygeneralizedseizuressuchasabsencesandmayaggravatethese

seizuresinsomepatients.Therefore,gabapentinshouldbeusedwithcautioninpatientswithmixedseizuresincluding

absences.

Nosystematicstudiesinpatients65yearsorolderhavebeenconductedwithgabapentin.Inonedoubleblindstudyin

patientswithneuropathicpain,somnolence,peripheraloedemaandastheniaoccurredinasomewhathigherpercentage

inpatientsaged65yearsorabove,thaninyoungerpatients.Apartfromthesefindings,clinicalinvestigationsinthis

Table2

DOSAGEOFGABAPENTININADULTSBASEDONRENALFUNCTION

CreatinineClearance(ml/min)

TotalDailyDose a

(mg/day)

≥80 900-3600

50-79 600-1800

30-49 300-900

15-29

-600

<15 c

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Theeffectsoflong-term(greaterthan36weeks)gabapentintherapyonlearning,intelligence,anddevelopmentin

childrenandadolescentshavenotbeenadequatelystudied.Thebenefitsofprolongedtherapymustthereforebe

weighedagainstthepotentialrisksofsuchtherapy.

Laboratorytests

Falsepositivereadingsmaybeobtainedinthesemi-quantitativedeterminationoftotalurineproteinbydipsticktests.It

isthereforerecommendedtoverifysuchapositivedipsticktestresultbymethodsbasedonadifferentanalytical

principlesuchastheBiuretmethod,turbidimetricordye-bindingmethods,ortousethesealternativemethodsfromthe

beginning.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inastudyinvolvinghealthyvolunteers(N=12),whena60mgcontrolled-releasemorphinecapsulewasadministered2

hourspriortoa600mggabapentincapsule,meangabapentinAreaUndertheCurve(AUC)increasedby44%

comparedtogabapentinadministeredwithoutmorphine.Therefore,patientsshouldbecarefullyobservedforsignsof

CNSdepression,suchassomnolence,andthedoseofgabapentinormorphineshouldbereducedappropriately.

Nointeractionbetweengabapentinandphenobarbital,phenytoin,valproicacid,orcarbamazepinehasbeenobserved.

Gabapentinsteady-statepharmacokineticsaresimilarforhealthysubjectsandpatientswithepilepsyreceivingthese

antiepilepticagents.

Co-administrationofgabapentinwithoralcontraceptivescontainingnorethindroneand/orethinylestradiol,doesnot

influencethesteady-statepharmacokineticsofeithercomponent.

Co-administrationofgabapentinwithantacidscontainingaluminiumandmagnesium,reducesgabapentin

bioavailabilityupto24%.Itisrecommendedthatgabapentinbetakenattheearliesttwohoursfollowingantacid

administration.

Renalexcretionofgabapentinisunalteredbyprobenecid.

Aslightdecreaseinrenalexcretionofgabapentinthatisobservedwhenitisco-administeredwithcimetidineisnot

expectedtobeofclinicalimportance.

4.6Pregnancyandlactation

Riskrelatedtoepilepsyandantiepilepticmedicinalproductsingeneral

Theriskofbirthdefectsisincreasedbyafactorof2–3intheoffspringofmotherstreatedwithanantiepileptic

medicinalproduct.Mostfrequentlyreportedarecleftlip,cardiovascularmalformationsandneuraltubedefects.

Multipleantiepilepticdrugtherapymaybeassociatedwithahigherriskofcongenitalmalformationsthan

monotherapy,thereforeitisimportantthatmonotherapyispractisedwheneverpossible.Specialistadviceshouldbe

giventowomenwhoarelikelytobecomepregnantorwhoareofchildbearingpotentialandtheneedforantiepileptic

treatmentshouldbereviewedwhenawomanisplanningtobecomepregnant.Nosuddendiscontinuationof

antiepileptictherapyshouldbeundertakenasthismayleadtobreakthroughseizures,whichcouldhaveserious

consequencesforbothmotherandchild.Developmentaldelayinchildrenofmotherswithepilepsyhasbeenobserved

rarely.Itisnotpossibletodifferentiateifthedevelopmentaldelayiscausedbygenetic,socialfactors,maternal

epilepsyortheantiepileptictherapy.

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Therearenoadequatedatafromtheuseofgabapentininpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Gabapentinshouldnotbeusedduringpregnancyunlessthepotentialbenefittothemotherclearlyoutweighsthe

potentialrisktothefoetus.

Nodefiniteconclusioncanbemadeastowhethergabapentinisassociatedwithanincreasedriskofcongenital

malformationswhentakenduringpregnancy,becauseofepilepsyitselfandthepresenceofconcomitantantiepileptic

medicinalproductsduringeachreportedpregnancy.

Gabapentinisexcretedinhumanmilk.Becausetheeffectonthebreast-fedinfantisunknown,cautionshouldbe

exercisedwhengabapentinisadministeredtoabreast-feedingmother.Gabapentinshouldbeusedinbreast-feeding

mothersonlyifthebenefitsclearlyoutweightherisks.

4.7Effectsonabilitytodriveandusemachines

Gabapentinmayhaveminorormoderateinfluenceontheabilitytodriveandusemachines.Gabapentinactsonthe

centralnervoussystemandmaycausedrowsiness,dizzinessorotherrelatedsymptoms.Even,iftheywereonlyofmild

ormoderatedegree,theseundesirableeffectscouldbepotentiallydangerousinpatientsdrivingoroperatingmachinery.

Thisisespeciallytrueatthebeginningofthetreatmentandafterincreaseindose.

4.8Undesirableeffects

Theadversereactionsobservedduringclinicalstudiesconductedinepilepsy(adjunctiveandmonotherapy)and

neuropathicpainhavebeenprovidedinasinglelistbelowbyclassandfrequency(verycommon(>1/10),common

(>1/100,<1/10),uncommon(>1/1000,<1/100)andrare(>1/10,000;<1/1,000).Whereanadversereactionwasseenat

differentfrequenciesinclinicalstudies,itwasassignedtothehighestfrequencyreported.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Infectionsandinfestations

Bloodandthelymphaticsystemdisorders

Immunesystemdisorders

MetabolismandNutritionDisorders

VeryCommon: Viralinfection.

Common: Pneumonia,respiratoryinfection,urinarytractinfection,infection,

otitismedia.

Common: leucopoenia.

Rare: thrombocytopenia.

Rare: allergicreactions(e.g.urticaria).

Common: anorexia,increasedappetite.

Common: hostility,confusionandemotionallability,depression,anxiety,

nervousness,thinkingabnormal.

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Nervoussystemdisorders

Eyedisorders

EarandLabyrinthdisorders

Cardiacdisorders

Vasculardisorder

Respiratory,thoracicandmediastinaldisorders

Gastrointestinaldisorders

Hepatobiliarydisorders

Skinandsubcutaneoustissuedisorders

Musculoskeletal,connectivetissueandbonedisorders

VeryCommon: somnolence,dizziness,ataxia.

Common: convulsions,hyperkinesias,dysarthria,amnesia,tremor,insomnia,

headache,sensationssuchasparaesthesia,hypaesthesia,

coordinationabnormal,nystagmus,increased,decreased,orabsent

reflexes.

Rare: movementdisorders(e.g.choreoathetosis,dyskinesia,dystonia).

Common: visualdisturbancessuchasamblyopia,diplopia.

Common: vertigo.

Rare: tinnitus.

Rare: palpitations.

Common: hypertension,vasodilatation.

Common: dyspnoea,bronchitis,pharyngitis,cough,rhinitis.

Common: vomiting,nausea,dentalabnormalities,gingivitis,diarrhoea,abdominal

pain,dyspepsia,constipation,drymouthorthroat,flatulence.

Rare: pancreatitis.

Rare: hepatitis,jaundice.

Common: facialoedema,purpuramostoftendescribedasbruisesresultingfrom

physicaltrauma,rash,pruritus,acne.

Rare: Stevens-Johnsonsyndrome,angioedema,erythemamultiforme,

alopecia.

Common arthralgia,myalgia,backpain,twitching.

Common: incontinence.

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Reproductivesystemandbreastdisorders

Generaldisordersandadministrationsiteconditions

Investigations

Injuryandpoisoning

Undertreatmentwithgabapentincasesofacutepancreatitiswerereported.Causalitywithgabapentinisunclear(see

section4.4).

Respiratorytractinfections,otitismedia,convulsionsandbronchitiswerereportedonlyinclinicalstudiesinchildren.

Additionally,inclinicalstudiesinchildren,aggressivebehaviourandhyperkinesiaswerereportedcommonly.

4.9Overdose

Acute,life-threateningtoxicityhasnotbeenobservedwithgabapentinoverdosesofupto49g.Symptomsofthe

overdosesincludeddizziness,doublevision,slurredspeech,drowsiness,lethargyandmilddiarrhoea.Allpatients

recoveredfullywithsupportivecare.Reducedabsorptionofgabapentinathigherdosesmaylimitdrugabsorptionat

thetimeofoverdosingand,hence,minimizetoxicityfromoverdoses.

Althoughgabapentincanberemovedbyhaemodialysis,basedonpriorexperienceitisusuallynotrequired.However,

inpatientswithsevererenalimpairment,haemodialysismaybeindicated.

Anorallethaldoseofgabapentinwasnotidentifiedinmiceandratsgivendosesashighas8000mg/kg.Signsofacute

toxicityinanimalsincludedataxia,labouredbreathing,ptosis,hypoactivity,orexcitation.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroups:Otheranti-epilepticsATCcode:N03AX12.

Theprecisemechanismofactionofgabapentinisnotknown.

GabapentinisstructurallyrelatedtotheneurotransmitterGABA(gamma-aminobutyricacid)butitsmechanismof

actionisdifferentfromthatofseveralotheractivesubstancesthatinteractwithGABAsynapsesincludingvalproate,

barbiturates,benzodiazepines,GABAtransaminaseinhibitors,GABAuptakeinhibitors,GABAagonists,andGABA

prodrugs.Invitrostudieswithradiolabeledgabapentinhavecharacterizedanovelpeptidebindingsiteinratbrain

tissuesincludingneocortexandhippocampusthatmayrelatetoanticonvulsantandanalgesicactivityofgabapentinand

Common: impotence.

VeryCommon: fatigue,fever.

Common: peripheralorgeneralizedoedema,abnormalgait,asthenia,pain,

malaise,flusyndrome.

Rare: withdrawalreactions(mostlyanxiety,insomnia,nausea,pains,

sweating),chestpain.Suddenunexplaineddeathshavebeen

reportedwhereacausalrelationshiptotreatmentwithgabapentin

hasnotbeenestablished.

Common: WBC(whitebloodcellcount)decreased,weightgain.

Rare: bloodglucosefluctuationsinpatientswithdiabetes,elevatedliverfunction

tests.

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gatedcalciumchannels.

Gabapentinatrelevantclinicalconcentrationsdoesnotbindtoothercommondrugorneurotransmitterreceptorsofthe

brainincludingGABAA,GABAB,benzodiazepine,glutamate,glycineorN-methyl-daspartatereceptors.

Gabapentindoesnotinteractwithsodiumchannelsinvitroandsodiffersfromphenytoinandcarbamazepine.

GabapentinpartiallyreducesresponsestotheglutamateagonistN-methyl-D-aspartate(NMDA)insometestsystemsin

vitro,butonlyatconcentrationsgreaterthan100µM,whicharenotachievedinvivo.Gabapentinslightlyreducesthe

releaseofmonoamineneurotransmittersinvitro.GabapentinadministrationtoratsincreasesGABAturnoverinseveral

brainregionsinamannersimilartovalproatesodium,althoughindifferentregionsofbrain.Therelevanceofthese

variousactionsofgabapentintotheanticonvulsanteffectsremainstobeestablished.Inanimals,gabapentinreadily

entersthebrainandpreventsseizuresfrommaximalelectroshock,fromchemicalconvulsantsincludinginhibitorsof

GABAsynthesis,andingeneticmodelsofseizures.

Aclinicaltrialofadjunctivetreatmentofpartialseizuresinpaediatricsubjects,ranginginagefrom3to12years,

showedanumericalbutnotstatisticallysignificantdifferenceinthe50%responderrateinfavourofthegabapentin

groupcomparedtoplacebo.Additionalpost-hocanalysesoftheresponderratesbyagedidnotrevealastatistically

significanteffectofage,eitherasacontinuousordichotomousvariable(agegroups3-5and6-12years).Thedatafrom

thisadditionalpost-hocanalysisaresummarisedinthetablebelow:

*Themodifiedintenttotreatpopulationwasdefinedasallpatientsrandomisedtostudymedicationwhoalsohad

evaluableseizurediariesavailablefor28daysduringboththebaselineanddouble-blindphases.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,peakplasmagabapentinconcentrationsareobservedwithin2to3hours.Gabapentin

bioavailability(fractionofdoseabsorbed)tendstodecreasewithincreasingdose.Absolutebioavailabilityofa300mg

capsuleisapproximately60%.Food,includingahigh-fatdiet,hasnoclinicallysignificanteffectongabapentin

pharmacokinetics.

Gabapentinpharmacokineticsarenotaffectedbyrepeatedadministration.Althoughplasmagabapentinconcentrations

weregenerallybetween2micrograms/mland20micrograms/mlinclinicalstudies,suchconcentrationswerenot

Response(50%Improved)byTreatmentandAgeMITT*Population

AgeCategory Placebo Gabapentin P-Value

<6YearsOld 4/21(19.0%) 4/17(23.5%) 0.7362

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=Maximumsteadystateplasmaconcentration.

=TimeforC

max.

T1/2=Eliminationhalf-life.

AUC(0-8)=Steadystateareaunderplasmaconcentration-timecurvefromtime0to8hourspostdose.

Ae%=Percentofdoseexcretedunchangedintotheurinefromtime0to8hourspostdose.

NA=Notavailable.

Distribution

Gabapentinisnotboundtoplasmaproteinsandhasavolumeofdistributionequalto57.7litres.Inpatientswith

epilepsy,gabapentinconcentrationsincerebrospinalfluid(CSF)areapproximately20%ofcorrespondingsteady-state

troughplasmaconcentrations.Gabapentinispresentinthebreastmilkofbreast-feedingwomen.

Metabolism

Thereisnoevidenceofgabapentinmetabolisminhumans.Gabapentindoesnotinducehepaticmixedfunctionoxidase

enzymesresponsiblefordrugmetabolism.

Elimination

Gabapentiniseliminatedunchangedsolelybyrenalexcretion.Theeliminationhalf-lifeofgabapentinisindependentof

doseandaverages5to7hours.

Inelderlypatients,andinpatientswithimpairedrenalfunction,gabapentinplasmaclearanceisreduced.Gabapentin

elimination-rateconstant,plasmaclearance,andrenalclearancearedirectlyproportionaltocreatinineclearance.

Gabapentinisremovedfromplasmabyhaemodialysis.Dosageadjustmentinpatientswithcompromisedrenalfunction

orundergoinghaemodialysisisrecommended(seesection4.2).

Gabapentinpharmacokineticsinchildrenweredeterminedin50healthysubjectsbetweentheagesof1monthand12

years.Ingeneral,plasmagabapentinconcentrationsinchildren>5yearsofagearesimilartothoseinadultswhen

dosedonamg/kgbasis.

Linearity/Non-linearity

Gabapentinbioavailability(fractionofdoseabsorbed)decreaseswithincreasingdosewhichimpartsnon-linearityto

pharmacokineticparameterswhichincludethebioavailabilityparameter(F)e.g.Ae%,CL/F,Vd/F.Elimination

pharmacokinetics(pharmacokineticparameterswhichdonotincludeFsuchasCLrandT1/2),arebestdescribedby

Table3

Summaryofgabapentinmean(%CV)steady-statepharmacokineticparameters

followingeveryeighthoursadministration

Pharmacokinetic

parameter 300mg

(N=7) 400mg

(N=14) 800mg

(N=14)

Mean %CV Mean %CV Mean %CV

(µg/ml) 4.02 (24) 5.74 (38) 8.71 (29)

(hr) 2.7 (18) 2.1 (54) 1.6 (76)

T1/2(hr) 5.2 (12) 10.8 (89) 10.6 (41)

AUC(0-8)

(µg hr/ml) 24.8 (24) 34.5 (34) 51.4 (27)

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5.3Preclinicalsafetydata

Carcinogenesis

Gabapentinwasgiveninthediettomiceat200,600,and2000mg/kg/dayandtoratsat250,1000,and2000

mg/kg/dayfortwoyears.Astatisticallysignificantincreaseintheincidenceofpancreaticacinarcelltumorswasfound

onlyinmaleratsatthehighestdose.Peakplasmadrugconcentrationsinratsat2000mg/kg/dayare10timeshigher

thanplasmaconcentrationsinhumansgiven3600mg/day.Thepancreaticacinarcelltumorsinmaleratsarelow-grade

malignancies,didnotaffectsurvival,didnotmetastasizeorinvadesurroundingtissue,andweresimilartothoseseenin

concurrentcontrols.Therelevanceofthesepancreaticacinarcelltumorsinmaleratstocarcinogenicriskinhumansis

unclear.

Mutagenesis

Gabapentindemonstratednogenotoxicpotential.Itwasnotmutagenicinvitroinstandardassaysusingbacterialor

mammaliancells.Gabapentindidnotinducestructuralchromosomeaberrationsinmammaliancellsinvitroorinvivo,

anddidnotinducemicronucleusformationinthebonemarrowofhamsters.

ImpairmentofFertility

Noadverseeffectsonfertilityorreproductionwereobservedinratsatdosesupto2000mg/kg(approximatelyfive

timesthemaximumdailyhumandoseonamg/ m2

ofbodysurfaceareabasis).

Teratogenesis

Gabapentindidnotincreasetheincidenceofmalformations,comparedtocontrols,intheoffspringofmice,rats,or

rabbitsatdosesupto50,30and25timesrespectively,thedailyhumandoseof3600mg,(four,fiveoreighttimes,

respectively,thehumandailydoseonamg/ m2

basis).

Gabapentininduceddelayedossificationintheskull,vertebrae,forelimbs,andhindlimbsinrodents,indicativeof

foetalgrowthretardation.Theseeffectsoccurredwhenpregnantmicereceivedoraldosesof1000or3000mg/kg/day

duringorganogenesisandinratsgiven500,1000,or2000mg/kgpriortoandduringmatingandthroughoutgestation.

Thesedosesareapproximately1to5timesthehumandoseof3600mgonamg/m 2

basis.

Noeffectswereobservedinpregnantmicegiven500mg/kg/day(approximately1/2ofthedailyhumandoseona

mg/m 2

basis).

Anincreasedincidenceofhydroureterand/orhydronephrosiswasobservedinratsgiven2000mg/kg/dayinafertility

andgeneralreproductionstudy,1500mg/kg/dayinateratologystudy,and500,1000,and2000mg/kg/dayina

perinatalandpostnatalstudy.Thesignificanceofthesefindingsisunknown,buttheyhavebeenassociatedwith

delayeddevelopment.Thesedosesarealsoapproximately1to5timesthehumandoseof3600mgonamg/m 2

basis.

Inateratologystudyinrabbits,anincreasedincidenceofpost-implantationfoetalloss,occurredindosesgiven60,

300,and1500mg/kg/dayduringorganogenesis.Thesedosesareapproximately1/4to8timesthedailyhumandoseof

3600mgonamg/m 2

basis.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Maizestarch

PovidoneK30

Sodiumstarchglycollate

Irish Medicines Board

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Date Printed 10/05/2007 CRN 2036728 page number: 11

Talc

Sodiumlaurylsulphate

TabletCoating:

Opadrywhite(lactosemonohydrate,hypromellose,titaniumdioxide,macrogol4000)

Candelillawax

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

1year.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

ThetabletsarepackedinPVC/PVdC/alublisterpacks.

Packsizes:20,50,100,and200.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

WinthropArzneimittelGmbH

Industriestrasse26

56218Mülheim-Kärlich

Germany

8MARKETINGAUTHORISATIONNUMBER

PA1300/1/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:10March2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 10/05/2007 CRN 2036728 page number: 12