GABAPENTIN

Main information

  • Trade name:
  • GABAPENTIN Capsules Hard 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GABAPENTIN Capsules Hard 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1046/001/001
  • Authorization date:
  • 05-09-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1046/001/001

CaseNo:2074505

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

WinthropPharmaceuticalsUKLimited

OneOnslowStreet,Guildford,Surrey,GU14YS,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gabapentin,100Milligram

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom05/01/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 05/01/2010 CRN 2074505 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gabapentin100mgCapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each100mghardcapsulecontains100mgofgabapentin

Excipients:

Each100mghardcapsulecontains15.992mgoflactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard(capsule)

White,hardcapsules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Gabapentinisindicatedasadjunctivetherapyinthetreatmentofpartialseizureswithandwithoutsecondary

generalizationinadultsandchildrenaged6yearsandabove(seesection5.1).

Gabapentinisindicatedasmonotherapyinthetreatmentofpartialseizureswithandwithoutsecondarygeneralization

inadultsandadolescentsaged12yearsandabove.

Treatmentofperipheralneuropathicpain

Gabapentinisindicatedforthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-

herpeticneuralgiainadults.

4.2Posologyandmethodofadministration

Fororaluse.

Gabapentincanbegivenwithorwithoutfoodandshouldbeswallowedwholewithsufficientfluid-

intake(e.g.aglassofwater).

ForallindicationsatitrationschemefortheinitiationoftherapyisdescribedinTable1,whichisrecommendedfor

adultsandadolescentsaged12yearsandabove.Dosinginstructionsforchildren

under12yearsofageareprovidedunderaseparatesub-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-labelclinicalstudies.Thetotaldailydose

shouldbedividedinthreesingledoses,themaximumtimeintervalbetweenthedosesshouldnotexceed12hoursto

preventbreakthroughconvulsions.

Childrenaged6yearsandabove:

Thestartingdoseshouldrangefrom10to15mg/kg/dayandtheeffectivedoseisreachedbyupwardtitrationovera

periodofapproximatelythreedays.Theeffectivedoseofgabapentininchildrenaged6yearsandolderis25to35

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

shouldbedividedinthreesingledoses,themaximumtimeintervalbetweendosesshouldnotexceed12hours.

Itisnotnecessarytomonitorgabapentinplasmaconcentrationstooptimizegabapentintherapy.Further,gabapentinmaybeused

incombinationwithotherantiepilepticmedicinalproductswithoutconcernforalterationoftheplasmaconcentrationsof

gabapentinorserumconcentrationsofotherantiepilepticmedicinalproducts.

Peripheralneuropathicpain

Adults:

ThetherapymaybeinitiatedbytitratingthedoseasdescribedinTable1.Alternatively,thestarting

doseis900mg/daygivenasthreeequallydivideddoses.Thereafter,basedonindividualpatientresponseand

tolerability,thedosecanbefurtherincreasedin300mg/dayincrementsevery2-3daysuptoamaximumdoseof3600

mg/day.Slowertitrationofgabapentindosagemaybeappropriateforindividualpatients.Theminimumtimetoreacha

doseof1800mg/dayisoneweek,toreach2400mg/dayisa

totalof2weeks,andtoreach3600mg/dayisatotalof3weeks.

Inthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-herpeticneuralgia,efficacy

andsafetyhavenotbeenexaminedinclinicalstudiesfortreatmentperiodslonger

than5months.Ifapatientrequiresdosinglongerthan5monthsforthetreatmentofperipheralneuropathicpain,the

treatingphysicianshouldassessthepatient’sclinicalstatusanddeterminetheneedforadditionaltherapy.

Instructionforallareasofindication

Inpatientswithpoorgeneralhealth,i.e.,lowbodyweight,afterorgantransplantationetc.,thedose

shouldbetitratedmoreslowly,eitherbyusingsmallerdosagestrengthsorlongerintervalsbetweendosageincreases.

Useinelderlypatients(over65yearsofage)

Elderlypatientsmayrequiredosageadjustmentbecauseofdecliningrenalfunctionwithage(seeTable2).

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Useinpatientswithrenalimpairment

DosageadjustmentisrecommendedinpatientswithcompromisedrenalfunctionasdescribedinTable2and/orthose

undergoinghaemodialysis.Gabapentin100mgcapsulescanbeusedtofollowdosingrecommendationsforpatients

withrenalinsufficiency.

Totaldailydoseshouldbeadministeredasthreedivideddoses.Reduceddosagesareforpatientswithrenalimpairment

(creatinineclearance<79ml/min).

Tobeadministeredas300mgeveryotherday.

Forpatientswithcreatinineclearance<15ml/min,thedailydoseshouldbereducedinproportiontocreatinineclearance(e.g.,

patientswithacreatinineclearanceof7.5ml/minshouldreceiveone-halfthedailydosethatpatientswithacreatinineclearanceof

15ml/minreceive).

Useinpatientsundergoinghaemodialysis

Foranuricpatientsundergoinghaemodialysiswhohaveneverreceivedgabapentin,aloadingdoseof

300to400mg,then200to300mgofgabapentinfollowingeach4hoursofhaemodialysis,isrecommended.On

dialysis-freedays,thereshouldbenotreatmentwithgabapentin.

Forrenallyimpairedpatientsundergoinghaemodialysis,themaintenancedoseofgabapentinshouldbebasedonthe

dosingrecommendationsfoundinTable2.Inadditiontothemaintenancedose,an

additional200to300mgdosefollowingeach4-hourhaemodialysistreatmentisrecommended.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Ifapatientdevelopsacutepancreatitisundertreatmentwithgabapentin,discontinuationofgabapentinshouldbe

considered(seesection4.8).

Althoughthereisnoevidenceofreboundseizureswithgabapentin,abruptwithdrawalof

anticonvulsantsinepilepticpatientsmayprecipitatestatusepilepticus(seesection4.2).

Aswithotherantiepilepticmedicinalproducts,somepatientsmayexperienceanincreaseinseizurefrequencyorthe

onsetofnewtypesofseizureswithgabapentin.

Aswithotheranti-epileptics,attemptstowithdrawconcomitantanti-epilepticsintreatmentrefractorypatientsonmore

thanoneanti-epileptic,inordertoreachgabapentinmonotherapyhavealowsuccessrate.

Gabapentinisnotconsideredeffectiveagainstprimarygeneralizedseizuressuchasabsencesandmayaggravatethese

seizuresinsomepatients.Therefore,gabapentinshouldbeusedwithcautioninpatientswithmixedseizuresincluding

Table2

DOSAGEOFGABAPENTININADULTSBASEDONRENALFUNCTION

CreatinineClearance(ml/min)

TotalDailyDose a

(mg/day)

900-3600

50-79 600-1800

30-49 300-900

15-29

-600

<15 c

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Nosystematicstudiesinpatients65yearsorolderhavebeenconductedwithgabapentin.Inonedoubleblindstudyin

patientswithneuropathicpain,somnolence,peripheraloedemaandastheniaoccurredinasomewhathigherpercentage

inpatientsaged65yearsorabove,thaninyoungerpatients.Apartfromthesefindings,clinicalinvestigationsinthis

agegroupdonotindicateanadverseeventprofiledifferentfromthatobservedinyoungerpatients.

Theeffectsoflong-term(greaterthan36weeks)gabapentintherapyonlearning,intelligence,anddevelopmentin

childrenandadolescentshavenotbeenadequatelystudied.Thebenefitsofprolongedtherapymustthereforebe

weighedagainstthepotentialrisksofsuchtherapy.

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithanti-epilepticagentsinseveralindications.

Ameta-analyisisofrandomisedplacebo-controlledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedrisk

ofsuicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforgabapentin.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

Laboratorytests

Falsepositivereadingsmaybeobtainedinthesemi-quantitativedeterminationoftotalurineproteinbydipsticktests.It

isthereforerecommendedtoverifysuchapositivedipsticktestresultbymethodsbasedonadifferentanalytical

principlesuchastheBiuretmethod,turbidimetricordye-bindingmethods,ortousethesealternativemethodsfromthe

beginning.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucosegalactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inastudyinvolvinghealthyvolunteers(N=12),whena60mgcontrolled-releasemorphinecapsulewasadministered2

hourspriortoa600mggabapentincapsule,meangabapentinAUCincreasedby44%comparedtogabapentin

administeredwithoutmorphine.Therefore,patientsshouldbecarefullyobservedforsignsofCNSdepression,suchas

somnolence,andthedoseofgabapentinormorphineshouldbereducedappropriately.

Nointeractionbetweengabapentinandphenobarbital,phenytoin,valproicacid,orcarbamazepinehasbeenobserved.

Gabapentinsteady-statepharmacokineticsaresimilarforhealthysubjectsandpatientswithepilepsyreceivingthese

antiepilepticagents.

Coadministrationofgabapentinwithoralcontraceptivescontainingnorethindroneand/orethinylestradiol,doesnot

influencethesteady-statepharmacokineticsofeithercomponent.

Coadministrationofgabapentinwithantacidscontainingaluminiumandmagnesium,reducesgabapentin

bioavailabilityupto24%.Itisrecommendedthatgabapentinbetakenattheearliesttwohoursfollowingantacid

administration.

Renalexcretionofgabapentinisunalteredbyprobenecid.

Aslightdecreaseinrenalexcretionofgabapentinthatisobservedwhenitiscoadministeredwithcimetidineisnot

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4.6Pregnancyandlactation

Riskrelatedtoepilepsyandantiepilepticmedicinalproductsingeneral

Theriskofbirthdefectsisincreasedbyafactorof2–3intheoffspringofmotherstreatedwithanantiepileptic

medicinalproduct.Mostfrequentlyreportedarecleftlip,cardiovascularmalformationsandneuraltubedefects.

Multipleantiepilepticdrugtherapymaybeassociatedwithahigherriskof

congenitalmalformationsthanmonotherapy,thereforeitisimportantthatmonotherapyispractisedwheneverpossible.

Specialistadviceshouldbegiventowomenwhoarelikelytobecomepregnantor

whoareofchildbearingpotentialandtheneedforantiepileptictreatmentshouldbereviewedwhenawomanis

planningtobecomepregnant.Nosuddendiscontinuationofantiepileptictherapyshouldbeundertakenasthismaylead

tobreakthroughseizures,whichcouldhaveseriousconsequencesforbothmotherandchild.Developmentaldelayin

childrenofmotherswithepilepsyhasbeenobservedrarely.

Itisnotpossibletodifferentiateifthedevelopmentaldelayiscausedbygenetic,socialfactors,maternalepilepsyorthe

antiepileptictherapy.

Riskrelatedtogabapentin

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,iftheywereonlyofmildormoderatedegree,theseundesirableeffectscouldbepotentiallydangerousinpatients

drivingoroperatingmachinery.Thisisespeciallytrueatthebeginningofthetreatmentandafterincreaseindose.

4.8Undesirableeffects

Theadversereactionsobservedduringclinicalstudiesconductedinepilepsy(adjunctiveandmonotherapy)and

neuropathicpainhavebeenprovidedinasinglelistbelowbyclassandfrequency

(verycommon(1/10),common(1/100to<1/10),uncommon(1/1000to1/100)andrare(1/10,000to1/1,000).

Whereanadversereactionwasseenatdifferentfrequenciesinclinicalstudies,itwasassignedtothehighestfrequency

reported.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Infectionsandinfestations

VeryCommon: Viralinfection

Common: Pneumonia,respiratoryinfection,urinarytractinfection,infection,otitismedia

Bloodandthelymphaticsystemdisorders

Common: leucopenia

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Immunesystemdisorders

Rare: allergicreactions(e.g.urticaria)

MetabolismandNutritionDisorders

Common: anorexia,increasedappetite

Psychiatricdisorders

Common: hostility,confusionandemotionallability,depression,anxiety,nervousness,thinkingabnormal

Rare: hallucinations

Nervoussystemdisorders

VeryCommon: somnolence,dizziness,ataxia,

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

paresthesia,hypaesthesia,coordinationabnormal,nystagmus,increased,decreased,orabsent

reflexes

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

Eyedisorders

Common: visualdisturbancessuchasamblyopia,diplopia

EarandLabyrinthdisorders

Common: vertigo

Rare: tinnitus

Cardiacdisorders

Rare: palpitations

Vasculardisorder

Common: hypertension,vasodilatation

Respiratory,thoracicandmediastinaldisorders

Common: dyspnoea,bronchitis,pharyngitis,cough,rhinitis

Gastrointestinaldisorders

Common: vomiting,nausea,dentalabnormalities,gingivitis,diarrhea,abdominalpain,dyspepsia,

constipation,drymouthorthroat,flatulence

Rare: pancreatitis

Hepatobiliarydisorders

Rare: hepatitis,jaundice

Skinandsubcutaneoustissuedisorders

Common: facialoedema,purpuramostoftendescribedasbruisesresultingfromphysicaltrauma,rash,

pruritus,acne

Rare: Stevens-Johnsonsyndrome,angioedema,erythemamultiforme,alopecia

Musculoskeletal,connectivetissueandbonedisorders

Common: arthralgia,myalgia,backpain,twitching

Renalandurinarydisorders

Common: incontinence

Rare: acuterenalfailure

Reproductivesystemandbreastdisorders

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Generaldisordersandadministrationsiteconditions

VeryCommon: fatigue,fever

Common: peripheralorgeneralizedoedema,abnormalgait,asthenia,pain,malaise,flusyndrome

Rare: withdrawalreactions(mostlyanxiety,insomnia,nausea,pains,sweating),chestpain.Sudden

unexplaineddeathshavebeenreportedwhereacausalrelationshiptotreatmentwithgabapentin

hasnotbeenestablished.

Investigations

Common: WBC(whitebloodcellcount)decreased,weightgain

Rare: Bloodglucosefluctuationsinpatientswithdiabetes,elevatedliverfunctiontests

Injuryandpoisoning

Common: accidentalinjury,fracture,abrasion

Undertreatmentwithgabapentincasesofacutepancreatitiswerereported.Causalitywithgabapentinisunclear(see

section4.4).

Respiratorytractinfections,otitismedia,convulsionsandbronchitiswerereportedonlyinclinical

studiesinchildren.Additionally,inclinicalstudiesinchildren,aggressivebehaviourandhyperkinesiaswerereported

commonly.

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:Otherantiepileptics

ATCcode:N03AX12

Theprecisemechanismofactionofgabapentinisnotknown.

GabapentinisstructurallyrelatedtotheneurotransmitterGABA(gamma-aminobutyricacid)butitsmechanismof

actionisdifferentfromthatofseveralotheractivesubstancesthatinteractwithGABAsynapsesincludingvalproate,

barbiturates,benzodiazepines,GABAtransaminaseinhibitors,GABAuptakeinhibitors,GABAagonists,andGABA

prodrugs.Invitrostudieswithradiolabeledgabapentinhavecharacterizedanovelpeptidebindingsiteinratbrain

tissuesincludingneocortexandhippocampusthatmayrelatetoanticonvulsantandanalgesicactivityofgabapentinand

itsstructuralderivatives.Thebindingsiteforgabapentinhasbeenidentifiedasthealpha2-deltasubunitofvoltage-

gatedcalciumchannels.

Gabapentinatrelevantclinicalconcentrationsdoesnotbindtoothercommondrugorneurotransmitterreceptorsofthe

brainincludingGABA

,GABA

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Gabapentindoesnotinteractwithsodiumchannelsinvitroandsodiffersfromphenytoinandcarbamazepine.

GabapentinpartiallyreducesresponsestotheglutamateagonistN-methyl-D-aspartate(NMDA)insometestsystemsin

vitro,butonlyatconcentrationsgreaterthan100 µ

M,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

weregenerallybetween2 µ

g/mland20 µ

g/mlinclinicalstudies,suchconcentrationswerenotpredictiveofsafetyor

efficacy.PharmacokineticparametersaregiveninTable3.

Cmax=Maximumsteadystateplasmaconcentration

tmax=TimeforCmax

T1/2=Eliminationhalf-life

AUC(0-8)=Steadystateareaunderplasmaconcentration-timecurvefromtime0to8hourspostdose

Ae%=Percentofdoseexcretedunchangedintotheurinefromtime0to8hourspostdose

Response( ≥50%Improved)byTreatmentandAgeMITT*Population

AgeCategory Placebo Gabapentin P-Value

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

6to12YearsOld 17/99(17.2%) 20/96(20.8%) 0.5144

Table3

Summaryofgabapentinmean(%CV)steady-statepharmacokineticparameters

followingeveryeighthoursadministration

Pharmacokinetic

parameter 300mg

(N=7) 400mg

(N=14) 800mg

(N=14)

Mean %CV Mean %CV Mean %CV

Cmax µ

g/ml) 4.02 (24) 5.74 (38) 8.71 (29)

tmax(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) 24.8 (24) 34.5 (34) 51.4 (27)

hr/ml)

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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

linearpharmacokinetics.Steadystateplasmagabapentinconcentrationsarepredictablefromsingle-dosedata.

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/m 2

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Teratogenesis

Gabapentindidnotincreasetheincidenceofmalformations,comparedtocontrols,intheoffspringofmice,rats,or

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

respectively,thehumandailydoseonamg/m 2

basis).

Gabapentininduceddelayedossificationintheskull,vertebrae,forelimbs,andhindlimbsinrodents,indicativeoffetal

growthretardation.Theseeffectsoccurredwhenpregnantmicereceivedoraldosesof1000or3000mg/kg/dayduring

organogenesisandinratsgiven500,1000,or2000mg/kgpriortoandduringmatingandthroughoutgestation.These

dosesareapproximately1to5timesthehumandoseof3600mgonamg/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-implantationfetalloss,occurredindosesgiven60,300,

and1500mg/kg/dayduringorganogenesis.Thesedosesareapproximately1/4to8timesthedailyhumandoseof3600

mgonamg/m 2

basis.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents:

Lactosemonohydrate

Maizestarch

Talc

Capsuleshell:

Titaniumdioxide(E171)

Gelatin

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Storagecondition

Thismedicinalproductdoesnotrequireanyspecialtemperaturestorageconditions.

Irish Medicines Board

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Date Printed 05/01/2010 CRN 2074505 page number: 11

6.5Natureandcontentsofcontainer

ThecapsulesarepackedinPVC/aluminiumblister.

Packsizes: 20,50,84,100,200and500.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

WinthropPharmaceuticalsUKLtd

OneOnslowStreet

Guildford

Surrey

GUI4YS

UnitedKingdom

Tradingas:

WinthropPharmaceuticals

POBox611

Guildford

Surrey

GU14YS

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1046/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5 th

September2003

Dateoflastrenewal:26 th

September2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 05/01/2010 CRN 2074505 page number: 12