GABAPENTIN 300MG CAPSULES

Main information

  • Trade name:
  • GABAPENTIN 300MG CAPSULES
  • Dosage:
  • 300 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GABAPENTIN 300MG CAPSULES
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1097/001/002
  • Authorization date:
  • 10-06-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PA1097/001/002

CaseNo:2027938

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Lexon(UK)Ltd

Unit18,OxleasowRoad,EastMoonsMoat,WorcestershireB980RE,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gabapentin300mgCapsules

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom31/10/2006until09/06/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 01/11/2006 CRN 2027938 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gabapentin300mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each300mghardcapsulecontains300mgofgabapentin.

Each300mghardcapsulecontains41mglactose(asmonohydrate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

Ayellowopaquehardgelatincapsule.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Gabapentinisindicatedasadjunctivetherapyinthetreatmentofpartialseizureswithandwithoutsecondarygeneralizationin

adultsandchildrenaged6yearsandabove(seesection5.1).

Gabapentinisindicatedasmonotherapyinthetreatmentofpartialseizureswithandwithoutsecondarygeneralizationinadults

andadolescentsaged12yearsandabove.

Treatmentofperipheralneuropathicpain

Gabapentinisindicatedforthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-herpetic

neuralgiainadults.

4.2Posologyandmethodofadministration

Fororaluse.

Gabapentincanbegivenwithorwithoutfoodandshouldbeswallowedwholewithsufficientfluid-intake(e.g.aglassofwater).

ForallindicationsatitrationschemefortheinitiationoftherapyisdescribedinTable1,whichisrecommendedforadultsand

adolescentsaged12yearsandabove.Dosinginstructionsforchildrenunder12yearsofageareprovidedunderaseparatesub-

headinglaterinthissection.

Table1

DOSINGCHART–INITIALTITRATION

Day1 Day2 Day3

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Epilepsy

Epilepsytypicallyrequireslong-termtherapy.Dosageisdeterminedbythetreatingphysicianaccordingtoindividualtolerance

andefficacy.Wheninthejudgmentoftheclinicianthereisaneedfordosereduction,discontinuation,orsubstitutionwithan

alternativemedication,thisshouldbedonegraduallyoveraminimumofoneweek.

AdultsandAdolescents:

Inclinicaltrials,theeffectivedosingrangewas900to3600mg/day.Therapymaybeinitiatedbytitratingthedoseasdescribedin

Table1orbyadministering300mgthreetimesaday(TID)onDay1.Thereafter,basedonindividualpatientresponseand

tolerability,thedosecanbefurtherincreasedin300mg/dayincrementsevery2-3daysuptoamaximumdoseof3600mg/day.

Slowertitrationofgabapentindosagemaybeappropriateforindividualpatients.Theminimumtimetoreachadoseof1800

mg/dayisoneweek,toreach2400mg/dayisatotalof2weeks,andtoreach3600mg/dayisatotalof3weeks.Dosagesupto

4800mg/dayhavebeenwelltoleratedinlong-termopen-labelclinicalstudies.Thetotaldailydoseshouldbedividedinthree

singledoses,themaximumtimeintervalbetweenthedosesshouldnotexceed12hourstopreventbreakthroughconvulsions.

Childrenaged6yearsandabove:

Thestartingdoseshouldrangefrom10to15mg/kg/dayandtheeffectivedoseisreachedbyupwardtitrationoveraperiodof

approximatelythreedays.Theeffectivedoseofgabapentininchildrenaged6yearsandolderis25to35mg/kg/day.Dosagesup

to50mg/kg/dayhavebeenwelltoleratedinalong-termclinicalstudy.Thetotaldailydoseshouldbedividedinthreesingle

doses,themaximumtimeintervalbetweendosesshouldnotexceed12hours.

Itisnotnecessarytomonitorgabapentinplasmaconcentrationstooptimizegabapentintherapy.Further,gabapentinmaybeused

incombinationwithotherantiepilepticmedicinalproductswithoutconcernforalterationoftheplasmaconcentrationsof

gabapentinorserumconcentrationsofotherantiepilepticmedicinalproducts.

PeripheralNeuropathicPain

Adults

ThetherapymaybeinitiatedbytitratingthedoseasdescribedinTable1.Alternatively,thestartingdoseis900mg/daygivenas

threeequallydivideddoses.Thereafter,basedonindividualpatientresponseandtolerability,thedosecanbefurtherincreasedin

300mg/dayincrementsevery2-3daysuptoamaximumdoseof3600mg/day.Slowertitrationofgabapentindosagemaybe

appropriateforindividualpatients.Theminimumtimetoreachadoseof1800mg/dayisoneweek,toreach2400mg/dayisa

totalof2weeks,andtoreach3600mg/dayisatotalof3weeks.

Inthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-herpeticneuralgia,efficacyandsafety

havenotbeenexaminedinclinicalstudiesfortreatmentperiodslongerthan5months.Ifapatientrequiresdosinglongerthan5

monthsforthetreatmentofperipheralneuropathicpain,thetreatingphysicianshouldassessthepatient’sclinicalstatusand

determinetheneedforadditionaltherapy.

Instructionforallareasofindication

Inpatientswithpoorgeneralhealth,i.e.,lowbodyweight,afterorgantransplantationetc.,thedoseshouldbetitratedmoreslowly,

eitherbyusingsmallerdosagestrengthsorlongerintervalsbetweendosageincreases.

ElderlyPatients(over65yearsofage)

Elderlypatientsmayrequiredosageadjustmentbecauseofdecliningrenalfunctionwithage(seeTable2).Somnolence,

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Patientswithrenalimpairment

DosageadjustmentisrecommendedinpatientswithcompromisedrenalfunctionasdescribedinTable2and/orthoseundergoing

haemodialysis.Vivapentin100mgcapsulescanbeusedtofollowdosingrecommendationsforpatientswithrenalinsufficiency.

Table2:MaintenancedosageofVivapentininadultswithreducedrenalfunction

Totaldailydoseshouldbeadministeredasathreedivideddoses.Reduceddosagesareforpatientswithrenalimpairment

(creatinineclearance<79ml/min).

Tobeadministeredas300mgeveryotherday.

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

patientswithacreatinineclearanceof7.5ml/minshouldreceiveone-halfthedailydosethatpatientswithacreatinineclearance

of15ml/minreceive).

Useinpatientsundergoinghaemodialysis

Foranuricpatientsundergoinghaemodialysiswhohaveneverreceivedgabapentin,aloadingdoseof300to400mgis

recommendedthen200to300mgofgabapentinfollowingeach4hoursofhaemodialysis.Ondialysis-freedays,thereshouldbe

notreatmentwithgabapentin.

Forrenallyimpairedpatientsundergoinghaemodialysis,themaintenancedoseofgabapentinshouldbebasedonthedosing

recommendationsfoundinTable2.Inadditiontothemaintenancedose,anadditional200to300mgdosefollowingeach4-hour

haemodialysistreatmentisrecommended.

4.3Contraindications

GabapentiniscontraindicatedinpatientswhoarehypersensitivetoGabapentinortotheproduct'scomponents.

4.4Specialwarningsandprecautionsforuse

Ifapatientdevelopsacutepancreatitisundertreatmentwithgabapentin,discontinuationofgabapentinshouldbeconsidered(see

section4.8).

AlthoughthereisnoevidenceofreboundseizureswithVivapentin,abruptwithdrawalofanticonvulsantagentsinepileptic

patientsmayprecipitatestatusepilepticus(seesection4.2).

Aswithotherantiepilepticmedicinalproducts,somepatientsmayexperienceanincreaseinseizurefrequencyortheonsetofnew

typesofseizureswithgabapentin.

Aswithotheranti-epileptics,attemptstowithdrawconcomitantanti-epilepticsintreatmentrefractorypatientsonmorethanone

anti-epileptic,inordertoreachgabapentinmonotherapyhavealowsuccessrate.

Gabapentinisnotconsideredeffectiveagainstprimarygeneralizedseizuressuchasabsencesandmayaggravatetheseseizuresin

Renalfunction

CreatinineClearance

(ml/minute) TotalDailyDose a

(mg/day)

80 900-3600

50-79 600-1800

30-49 300-900

15-29 150 b

-600

<15 c

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Nosystematicstudiesinpatients65yearsorolderhavebeenconductedwithgabapentin.Inonedoubleblindstudyinpatients

withneuropathicpain,somnolence,peripheraloedemaandastheniaoccurredinasomewhathigherpercentageinpatientsaged65

yearsorabove,thaninyoungerpatients.Apartfromthesefindings,clinicalinvestigationsinthisagegroupdonotindicatean

adverseeventprofiledifferentfromthatobservedinyoungerpatients.

Theeffectsoflong-term(greaterthan36weeks)gabapentintherapyonlearning,intelligence,anddevelopmentinchildrenand

adolescentshavenotbeenadequatelystudied.Thebenefitsofprolongedtherapymustthereforebeweighedagainstthepotential

risksofsuchtherapy.

Laboratorytests

Falsepositivereadingsmaybeobtainedinthesemi-quantitativedeterminationoftotalurineproteinbydipsticktests.Itis

thereforerecommendedtoverifysuchapositivedipsticktestresultbymethodsbasedonadifferentanalyticalprinciplesuchas

theBiuretmethod,turbidimetricordye-bindingmethods,ortousethesealternativemethodsfromthebeginning.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption

shouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inastudyinvolvinghealthyvolunteers(N=12),whena60mgcontrolled-releasemorphinecapsulewasadministered2hours

priortoa600mggabapentincapsule,meangabapentinAUCincreasedby44%comparedtogabapentinadministeredwithout

morphine.Therefore,patientsshouldbecarefullyobservedforsignsofCNSdepression,suchassomnolence,andthedoseof

gabapentinormorphineshouldbereducedappropriately.

NointeractionbetweenVivapentinandphenytoin,valproicacid,carbamazepineorphenobarbitalhasbeenobserved.

Gabapentinsteady-statepharmacokineticsaresimilarforhealthysubjectsandpatientswithepilepsyreceivingtheseantiepileptic

agents.

Co-administrationofVivapentinwithoralcontraceptivescontainingnorethindroneand/orethinylestradioldoesnotinfluencethe

steady-statepharmacokineticsofeithercomponent.

Vivapentin'sbioavailabilitycanbereducedupto24%whengivenatthesametimeasaluminiumandmagnesiumcontaining

antacids.ItisrecommendedthatVivapentinistakenabouttwohoursfollowinganysuchantacidadministration.

TheslightdecreaseinrenalexcretionofVivapentinobservedwhenco-administeredwithcimetidineisnotexpectedtobeof

clinicalimportance.

RenalexcretionofVivapentinisunalteredbyprobenecid.

4.6Pregnancyandlactation

Riskrelatedtoepilepsyandantiepilepticmedicinalproductsingeneral

Theriskofbirthdefectsisincreasedbyafactorof2–3intheoffspringofmotherstreatedwithanantiepilepticmedicinal

product.Mostfrequentlyreportedarecleftlip,cardiovascularmalformationsandneuraltubedefects.Multipleantiepilepticdrug

therapymaybeassociatedwithahigherriskofcongenitalmalformationsthanmonotherapy,thereforeitisimportantthat

monotherapyispractisedwheneverpossible.Specialistadviceshouldbegiventowomenwhoarelikelytobecomepregnantor

whoareofchildbearingpotentialandtheneedforantiepileptictreatmentshouldbereviewedwhenawomanisplanningto

becomepregnant.Nosuddendiscontinuationofantiepileptictherapyshouldbeundertakenasthismayleadtobreakthrough

seizures,whichcouldhaveseriousconsequencesforbothmotherandchild.Developmentaldelayinchildrenofmotherswith

epilepsyhasbeenobservedrarely.Itisnotpossibletodifferentiateifthedevelopmentaldelayiscausedbygenetic,socialfactors,

maternalepilepsyortheantiepileptictherapy.

Riskrelatedtogabapentin

Therearenoadequatedatafromtheuseofgabapentininpregnantwomen.

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shouldnotbeusedduringpregnancyunlessthepotentialbenefittothemotherclearlyoutweighsthepotentialrisktothefoetus.

Nodefiniteconclusioncanbemadeastowhethergabapentinisassociatedwithanincreasedriskofcongenitalmalformations

whentakenduringpregnancy,becauseofepilepsyitselfandthepresenceofconcomitantantiepilepticmedicinalproductsduring

eachreportedpregnancy.

Gabapentinisexcretedinhumanmilk.Becausetheeffectonthebreast-fedinfantisunknown,cautionshouldbeexercisedwhen

gabapentinisadministeredtoabreast-feedingmother.Gabapentinshouldbeusedinbreast-feedingmothersonlyifthebenefits

clearlyoutweightherisks.

4.7Effectsonabilitytodriveandusemachines

Vivapentinmayhaveminorormoderateinfluenceontheabilitytodriveandusemachines.Vivapentinactsonthecentralnervous

systemandmayproducedrowsiness,dizziness,orotherrelatedsymptoms.Theseotherwisemildormoderateadverseevents

couldbepotentiallydangerousinpatientsdrivingoroperatingmachinery.Thisisespeciallytrueatthebeginningofthetreatment

andafterincreaseindose.

4.8Undesirableeffects

Theadversereactionsobservedduringclinicalstudiesconductedinepilepsy(adjunctiveandmonotherapy)andneuropathicpain

havebeenprovidedinasinglelistbelowbyclassandfrequency(verycommon(1/10),common(1/100,<1/10),uncommon

1/1,000, 1/100)andrare( 1/10,000; 1/1,000).Whereanadversereactionwasseenatdifferentfrequenciesinclinical

studies,itwasassignedtothehighestfrequencyreported.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Infectionsandinfestations

VeryCommon: Viralinfection

Common: Pneumonia,respiratoryinfection,urinarytractinfection,infection,otitismedia

Bloodandthelymphaticsystemdisorders

Common: leucopenia

Rare: thrombocytopenia

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,sensationssuchasparesthesia,

hypaesthesia,coordinationabnormal,nystagmus,increased,decreased,orabsentreflexes

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

Eyedisorders

Common: visualdisturbancessuchasamblyopia,diplopia

EarandLabyrinthdisorders

Common: vertigo

Rare: tinnitus

Cardiacdisorders

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Vasculardisorder

Common: hypertension,vasodilatation

Respiratory,thoracicandmediastinaldisorders

Common: dyspnoea,bronchitis,pharyngitis,cough,rhinitis

Gastrointestinaldisorders

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

orthroat,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

Common: impotence

Generaldisordersandadministrationsiteconditions

VeryCommon: fatigue,fever

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

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

havebeenreportedwhereacausalrelationshiptotreatmentwithgabapentinhasnotbeenestablished.

Investigations

Common: WBC(whitebloodcellcount)decreased,weightgain

Rare: Bloodglucosefluctuationsinpatientswithdiabetes,elevatedliverfunctiontests

Injuryandpoisoning

Common: accidentalinjury,fracture,abrasion

Undertreatmentwithgabapentincasesofacutepancreatitiswerereported.Causalitywithgabapentinisunclear(seesection4.4).

Respiratorytractinfections,otitismedia,convulsionsandbronchitiswerereportedonlyinclinicalstudiesinchildren.

Additionally,inclinicalstudiesinchildren,aggressivebehaviourandhyperkinesiaswerereportedcommonly.

4.9Overdose

Acute,life-threateningtoxicityhasnotbeenobservedwithVivapentinoverdosesofupto49g.Symptomsoftheoverdoses

includeddizziness,doublevision,slurredspeech,drowsiness,lethargyandmilddiarrhoea.Allpatientsrecoveredfullywith

supportivecare.ReducedabsorptionofVivapentinathigherdosesmaylimitdrugabsorptionatthetimeofoverdosingand,hence,

minimisetoxicityfromoverdoses.

AlthoughVivapentincanberemovedbyhaemodialysisitisnotusuallyrequired.However,inpatientswithsevererenal

impairment,haemodialysismaybeindicated.

Anorallethaldoseofgabapentinwasnotidentifiedinmiceandratsgivendosesashighas8000mg/kg.Signsofacutetoxicityin

animalsincludedataxia,labouredbreathing,ptosis,hypoactivity,orexcitation.

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5.1Pharmacodynamicproperties

Pharmacotherapeuticgroups:OtherantiepilepticsATCcode:N03AX12

Theprecisemechanismofactionofgabapentinisnotknown.

Vivapentinisstructurallyrelatedtotheneurotransmittergamma-aminobutyricacid(GABA)butitsmechanismofactionis

differentfromthatofseveralotheractivesubstancesthatinteractwithGABAsynapsesincludingvalproate,barbiturates,

benzodiazepines,GABAtransaminaseinhibitors,GABAuptakeinhibitors,GABAagonists,andGABAprodrugs.Invitrostudies

withradiolabeledgabapentinhavecharacterizedanovelpeptidebindingsiteinratbraintissuesincludingneocortexand

hippocampusthatmayrelatetoanticonvulsantandanalgesicactivityofgabapentinanditsstructuralderivatives.Thebindingsite

forgabapentinhasbeenidentifiedasthealpha

-deltasubunitofvoltage-gatedcalciumchannels.

Gabapentinatrelevantclinicalconcentrationsdoesnotbindtoothercommondrugorneurotransmitterreceptorsofthebrain

includingGABA

,GABA

,benzodiazepine,glutamate,glycineorN-methyl-d-aspartatereceptors.

Gabapentindoesnotinteractwithsodiumchannelsinvitroandsodiffersfromphenytoinandcarbamazepine.Gabapentin

partiallyreducesresponsestotheglutamateagonistN-methyl-D-aspartate(NMDA)insometestsystemsinvitro,butonlyat

concentrationsgreaterthan100µM,whicharenotachievedinvivo.Gabapentinslightlyreducesthereleaseofmonoamine

neurotransmittersinvitro.GabapentinadministrationtoratsincreasesGABAturnoverinseveralbrainregionsinamannersimilar

tovalproatesodium,althoughindifferentregionsofbrain.Therelevanceofthesevariousactionsofgabapentintothe

anticonvulsanteffectsremainstobeestablished.Inanimals,gabapentinreadilyentersthebrainandpreventsseizuresfrom

maximalelectroshock,fromchemicalconvulsantsincludinginhibitorsofGABAsynthesis,andingeneticmodelsofseizures.

Aclinicaltrialofadjunctivetreatmentofpartialseizuresinpaediatricsubjects,ranginginagefrom3to12years,showeda

numericalbutnotstatisticallysignificantdifferenceinthe50%responderrateinfavourofthegabapentingroupcomparedto

placebo.Additionalpost-hocanalysesoftheresponderratesbyagedidnotrevealastatisticallysignificanteffectofage,eitheras

acontinuousordichotomousvariable(agegroups3-5and6-12years).Thedatafromthisadditionalpost-hocanalysisare

summarisedinthetablebelow:

Themodifiedintenttotreatpopulationwasdefinedasallpatientsrandomisedtostudymedicationwhoalsohadevaluable

seizurediariesavailablefor28daysduringboththebaselineanddouble-blindphases.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,peakplasmagabapentinconcentrationsareobservedwithin2to3hours.Gabapentin

bioavailability(fractionofdoseabsorbed)tendstodecreasewithincreasingdose.Absolutebioavailabilityofa300mgcapsuleis

approximately60%.Food,includingahigh-fatdiet,hasnoclinicallysignificanteffectongabapentinpharmacokinetics.

Gabapentinpharmacokineticsarenotaffectedbyrepeatedadministration.Althoughplasmagabapentinconcentrationswere

generallybetween2µg/mland20µg/mlinclinicalstudies,suchconcentrationswerenotpredictiveofsafetyorefficacy.

PharmacokineticparametersaregiveninTable3.

Table3

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

Pharmacokinetic 300mg 400mg 800mg

parameter (N=7) (N=14) (N=14)

Mean %CV Mean %CV Mean %CV

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Maximumsteadystateplasmaconcentration

TimeforC

T1/2 = Eliminationhalf-life

AUC(0-8)= Steadystateareaunderplasmaconcentration-timecurvefromtime0to8hourspostdose

Ae% = Percentofdoseexcretedunchangedintotheurinefromtime0to8hourspostdose

Notavailable

Distribution

Gabapentinisnotboundtoplasmaproteinsandhasavolumeofdistributionequalto57.7litres.Inpatientswithepilepsy,

gabapentinconcentrationsincerebrospinalfluid(CSF)areapproximately20%ofcorrespondingsteady-statetroughplasma

concentrations.Gabapentinispresentinthebreastmilkofbreast-feedingwomen.

Metabolism

Thereisnoevidenceofgabapentinmetabolisminhumans.Gabapentindoesnotinducehepaticmixedfunctionoxidaseenzymes

responsiblefordrugmetabolism.

Elimination

Gabapentiniseliminatedunchangedsolelybyrenalexcretion.Theeliminationhalf-lifeofgabapentinisindependentofdoseand

averages5to7hours.

Inelderlypatients,andinpatientswithimpairedrenalfunction,gabapentinplasmaclearanceisreduced.Gabapentinelimination-

rateconstant,plasmaclearance,andrenalclearancearedirectlyproportionaltocreatinineclearance.

Gabapentinisremovedfromplasmabyhaemodialysis.Dosageadjustmentinpatientswithcompromisedrenalfunctionor

undergoinghaemodialysisisrecommended(seesection4.2).

Gabapentinpharmacokineticsinchildrenweredeterminedin50healthysubjectsbetweentheagesof1monthand12years.In

general,plasmagabapentinconcentrationsinchildren>5yearsofagearesimilartothoseinadultswhendosedonamg/kgbasis.

Linearity/Non-linearity

Gabapentinbioavailability(fractionofdoseabsorbed)decreaseswithincreasingdosewhichimpartsnon-linearityto

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

(pharmacokineticparameterswhichdonotincludeFsuchasCLrandT1/2),arebestdescribedbylinearpharmacokinetics.Steady

stateplasmagabapentinconcentrationsarepredictablefromsingle-dosedata.

5.3Preclinicalsafetydata

Carcinogenesis

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

years.Astatisticallysignificantincreaseintheincidenceofpancreaticacinarcelltumourswasfoundonlyinmaleratsatthe

highestdose.Peakplasmadrugconcentrationsinratsat2000mg/kgare10timeshigherthanplasmaconcentrationsinhumans

given3600mg/day.

Thepancreaticacinarcelltumoursinmaleratsarelow-grademalignancies,theydidnotaffectsurvival,theydidnotmetastasise

orinvadesurroundingtissue,andweresimilartothoseseeninconcurrentcontrols.Therelevanceofthesepancreaticacinarcell

tumoursinmaleratstocarcinogenicriskinhumansisunclear.

(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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Gabapentindemonstratednogenotoxicpotential.Itwasnotmutagenicinvitroinstandardassaysusingbacterialormammalian

cells.Gabapentindidnotinducestructuralchromosomeaberrationsinmammaliancellsinvitroorinvivo,anddidnotinduce

micronucleusformationinthebonemarrowofhamsters.

ImpairmentofFertility

Noadverseeffectsonfertilityorreproductionwereobservedinratsatdosesupto2000mg/kg(approximatelyfivetimesthe

maximumdailyhumandoseonamg/m 2

ofbodysurfaceareabasis).

Teratogenesis

Gabapentindidnotincreasetheincidenceofmalformations,comparedtocontrols,intheoffspringofmice,rats,orrabbitsat

dosesupto50,30and25timesrespectively,thedailyhumandoseof3600mg,(four,fiveoreighttimes,respectively,thehuman

dailydoseonamg/m 2

basis).

Gabapentininduceddelayedossificationintheskull,vertebrae,forelimbs,andhindlimbsinrodents,indicativeoffetalgrowth

retardation.Theseeffectsoccurredwhenpregnantmicereceivedoraldosesof1000or3000mg/kg/dayduringorganogenesisand

inratsgiven500,1000,or2000mg/kgpriortoandduringmatingandthroughoutgestation.Thesedosesareapproximately1to5

timesthehumandoseof3600mgonamg/m 2

basis.

Noeffectswereobservedinpregnantmicegiven500mg/kg/day(approximately1/2ofthedailyhumandoseonamg/m 2

basis).

Anincreasedincidenceofhydroureterand/orhydronephrosiswasobservedinratsgiven2000mg/kg/dayinafertilityandgeneral

reproductionstudy,1500mg/kg/dayinateratologystudy,and500,1000,and2000mg/kg/dayinaperinatalandpostnatalstudy.

Thesignificanceofthesefindingsisunknown,buttheyhavebeenassociatedwithdelayeddevelopment.Thesedosesarealso

approximately1to5timesthehumandoseof3600mgonamg/m 2

basis.

Inateratologystudyinrabbits,anincreasedincidenceofpost-implantationfetalloss,occurredindosesgiven60,300,and1500

mg/kg/dayduringorganogenesis.Thesedosesareapproximately1/4to8timesthedailyhumandoseof3600mgonamg/m 2

basis.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Maizestarch

Talc

Capsuleshell

TitaniumDioxide(E171)

YellowIronOxide(E172)

Gelatin

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

TwoYears.

6.4Specialprecautionsforstorage

Irish Medicines Board

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Date Printed 01/11/2006 CRN 2027938 page number: 10

6.5Natureandcontentsofcontainer

30and100capsulesinPVC/Aluminiumblisterstrips.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

Lexon(UK)Ltd

Unit18

OxleasowRoad

EastMoonsMoat

Redditch

Worcestershire

B980RE

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1097/1/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10June2005

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 01/11/2006 CRN 2027938 page number: 11