GABIN 600 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • GABIN 600 MG FILM-COATED TABLETS
  • Dosage:
  • 600mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GABIN 600 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/132/004
  • Authorization date:
  • 30-03-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0711/132/004

CaseNo:2071609

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gabin600mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom25/02/2010until29/03/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gabin600mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains600mggabapentin

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet

Whitefilm-coatedtabletgroovedonbothsides.Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Gabapentinisindicatedasadjunctivetherapyinthetreatmentofpartialseizureswithandwithout

secondarygeneralizationinadultsandchildrenaged6yearsandabove(seesection5.1).

Gabapentinisindicatedasmonotherapyinthetreatmentofpartialseizureswithandwithoutsecondary

generalizationinadultsandadolescentsaged12yearsandabove.

Treatmentofperipheralneuropathicpain

Gabapentinisindicatedforthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-

herpeticneuralgiainadults.

4.2Posologyandmethodofadministration

Fororaluse.

Gabapentincanbegivenwithorwithoutfoodandshouldbeswallowedwholewithsufficientfluid-intake(e.g.aglass

ofwater).

ForallindicationsatitrationschemefortheinitiationoftherapyisdescribedinTable1,whichis

recommendedforadultsandadolescentsaged12yearsandabove.Dosinginstructionsforchildrenunder12yearsof

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Epilepsy

Epilepsytypicallyrequireslong-termtherapy.Dosageisdeterminedbythetreatingphysicianaccordingto

individualtoleranceandefficacy.Wheninthejudgmentoftheclinicianthereisaneedfordosereduction,

discontinuation,orsubstitutionwithanalternativemedication,thisshouldbedonegraduallyoveraminimumofone

week.

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,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

Table1

DOSINGCHART–INITIALTITRATION

Day1 Day2 Day3

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Instructionforallareasofindication

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

moreslowly,eitherbyusingsmallerdosagestrengthsorlongerintervalsbetweendosageincreases.

Useinelderlypatients(over65yearsofage)

Elderlypatientsmayrequiredosageadjustmentbecauseofdecliningrenalfunctionwithage(seeTable2).

Somnolence,peripheraloedemaandastheniamaybemorefrequentinelderlypatients.

Useinpatientswithrenalimpairment

DosageadjustmentisrecommendedinpatientswithcompromisedrenalfunctionasdescribedinTable2and/orthose

undergoinghaemodialysis.Gabapentin100mgcapsulescanbeusedtofollowdosingrecommendationsforpatients

withrenalinsufficiency.

Totaldailydoseshouldbeadministeredasthreedivideddoses.Reduceddosagesareforpatientswithrenal

impairment(creatinineclearance<79ml/min).

Tobeadministeredas300mgeveryotherday.

Forpatientswithcreatinineclearance<15ml/min,thedailydoseshouldbereducedinproportiontocreatinine

clearance(e.g.,patientswithacreatinineclearanceof7.5ml/minshouldreceiveone-halfthedailydosethatpatients

withacreatinineclearanceof15ml/minreceive).

Useinpatientsundergoinghaemodialysis

Foranuricpatientsundergoinghaemodialysiswhohaveneverreceivedgabapentin,aloadingdoseof300to400mg,

then200to300mgofgabapentinfollowingeach4hoursofhaemodialysis,isrecommended.Ondialysis-freedays,

thereshouldbenotreatmentwithgabapentin.

Forrenallyimpairedpatientsundergoinghaemodialysis,themaintenancedoseofgabapentinshouldbebasedonthe

dosingrecommendationsfoundinTable2.Inadditiontothemaintenancedose,anadditional200to300mgdose

followingeach4-hourhaemodialysistreatmentisrecommended.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Ifapatientdevelopsacutepancreatitisundertreatmentwithgabapentin,discontinuationofgabapentinshouldbe

Table2

DOSAGEOFGABAPENTININADULTSBASEDONRENALFUNCTION

CreatinineClearance(ml/min) TotalDailyDosea(mg/day)

≥80

900-3600

50-79 600-1800

30-49 300-900

15-29

-600

<15 c

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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

agegroupdonotindicateanadverseeventprofiledifferentfromthatobservedinyoungerpatients.

Theeffectsoflong-term(greaterthan36weeks)gabapentintherapyonlearning,intelligence,and

developmentinchildrenandadolescentshavenotbeenadequatelystudied.Thebenefitsofprolongedtherapymust

thereforebeweighedagainstthepotentialrisksofsuchtherapy.

Laboratorytests

Falsepositivereadingsmaybeobtainedinthesemi-quantitativedeterminationoftotalurineproteinbydipsticktests.It

isthereforerecommendedtoverifysuchapositivedipsticktestresultbymethodsbasedonadifferentanalytical

principlesuchastheBiuretmethod,turbidimetricordye-bindingmethods,ortousethesealternativemethodsfromthe

beginning.

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.

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Aslightdecreaseinrenalexcretionofgabapentinthatisobservedwhenitiscoadministeredwithcimetidineisnot

expectedtobeofclinicalimportance.

4.6Pregnancyandlactation

Riskrelatedtoepilepsyandantiepilepticmedicinalproductsingeneral

Theriskofbirthdefectsisincreasedbyafactorof2–3intheoffspringofmotherstreatedwithanantiepileptic

medicinalproduct.Mostfrequentlyreportedarecleftlip,cardiovascularmalformationsandneuraltubedefects.

Multipleantiepilepticdrugtherapymaybeassociatedwithahigherriskofcongenitalmalformationsthan

monotherapy,thereforeitisimportantthatmonotherapyispracticedwheneverpossible.Specialistadviceshouldbe

giventowomenwhoarelikelytobecomepregnantorwhoareofchildbearingpotentialandtheneedforantiepileptic

treatmentshouldbereviewedwhenawomanisplanningtobecomepregnant.Nosuddendiscontinuationof

antiepileptictherapyshouldbeundertakenasthismayleadtobreakthroughseizures,whichcouldhaveserious

consequencesforbothmotherandchild.Developmentaldelayinchildrenofmotherswithepilepsyhasbeenobserved

rarely.Itisnotpossibletodifferentiateifthedevelopmentaldelayiscausedbygenetic,socialfactors,maternal

epilepsyortheantiepileptictherapy.

Riskrelatedtogabapentin

Therearenoadequatedatafromtheuseofgabapentininpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Gabapentinshouldnotbeusedduringpregnancyunlessthepotentialbenefittothemotherclearlyoutweighsthe

potentialrisktothefoetus.

Nodefiniteconclusioncanbemadeastowhethergabapentinisassociatedwithanincreasedriskofcongenital

malformationswhentakenduringpregnancy,becauseofepilepsyitselfandthepresenceofconcomitantantiepileptic

medicinalproductsduringeachreportedpregnancy.

Gabapentinisexcretedinhumanmilk.Becausetheeffectonthebreast-fedinfantisunknown,cautionshouldbe

exercisedwhengabapentinisadministeredtoabreast-feedingmother.Gabapentinshouldbeusedinbreast-feeding

mothersonlyifthebenefitsclearlyoutweightherisks.

4.7Effectsonabilitytodriveandusemachines

Gabapentinmayhaveminorormoderateinfluenceontheabilitytodriveandusemachines.

Gabapentinactsonthecentralnervoussystemandmaycausedrowsiness,dizzinessorotherrelatedsymptoms.

Even,iftheywereonlyofmildormoderatedegree,theseundesirableeffectscouldbepotentially

dangerousinpatientsdrivingoroperatingmachinery.Thisisespeciallytrueatthebeginningofthetreatmentandafter

increaseindose.

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.

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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,or

absentreflexes

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

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Hepatobiliarydisorders

Rare: hepatitis,jaundice

Skinandsubcutaneoustissuedisorders

Common: facialoedema,purpuramostoftendescribedasbruisesresultingfrom

physicaltrauma,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.Suddenunexplaineddeathshavebeenreportedwhereacausal

relationshiptotreatmentwithgabapentinhasnotbeenestablished.

Investigations

Common: WBC(whitebloodcellcount)decreased,weightgain

Rare: Bloodglucosefluctuationsinpatientswithdiabetes,elevatedliverfunction

tests

Injuryandpoisoning

Common: accidentalinjury,fracture,abrasion

Undertreatmentwithgabapentincasesofacutepancreatitiswerereported.Causalitywithgabapentinisunclear(see

section4.4).

Respiratorytractinfections,otitismedia,convulsionsandbronchitiswerereportedonlyinclinicalstudiesinchildren.

Additionally,inclinicalstudiesinchildren,aggressivebehaviourandhyperkinesiaswerereportedcommonly.

4.9Overdose

Acute,life-threateningtoxicityhasnotbeenobservedwithgabapentinoverdosesofupto49g.Symptomsofthe

overdosesincludeddizziness,doublevision,slurredspeech,drowsiness,lethargyandmilddiarrhoea.

Allpatientsrecoveredfullywithsupportivecare.Reducedabsorptionofgabapentinathigherdosesmaylimitdrug

absorptionatthetimeofoverdosingand,hence,minimizetoxicityfromoverdoses.

Althoughgabapentincanberemovedbyhaemodialysis,basedonpriorexperienceitisusuallynotrequired.

However,inpatientswithsevererenalimpairment,haemodialysismaybeindicated.

Anorallethaldoseofgabapentinwasnotidentifiedinmiceandratsgivendosesashighas8000mg/kg.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroups:OtherantiepilepticsATCcode:N03AX12

Theprecisemechanismofactionofgabapentinisnotknown.

GabapentinisstructurallyrelatedtotheneurotransmitterGABA(gamma-aminobutyricacid)butitsmechanismof

actionisdifferentfromthatofseveralotheractivesubstancesthatinteractwithGABAsynapsesincludingvalproate,

barbiturates,benzodiazepines,GABAtransaminaseinhibitors,GABAuptakeinhibitors,GABAagonists,andGABA

prodrugs.Invitrostudieswithradiolabeledgabapentinhavecharacterizedanovelpeptidebindingsiteinratbrain

tissuesincludingneocortexandhippocampusthatmayrelatetoanticonvulsantandanalgesicactivityofgabapentinand

itsstructuralderivatives.Thebindingsiteforgabapentinhasbeenidentifiedasthealpha2-deltasubunitofvoltage-

gatedcalciumchannels.

Gabapentinatrelevantclinicalconcentrationsdoesnotbindtoothercommondrugorneurotransmitterreceptorsofthe

brainincludingGABA

,GABA

,benzodiazepine,glutamate,glycineorN-methyl-daspartatereceptors.

Gabapentindoesnotinteractwithsodiumchannelsinvitroandsodiffersfromphenytoinand

carbamazepine.GabapentinpartiallyreducesresponsestotheglutamateagonistN-methyl-D-aspartate(NMDA)in

sometestsystemsinvitro,butonlyatconcentrationsgreaterthan100µM,whicharenotachievedinvivo.Gabapentin

slightlyreducesthereleaseofmonoamineneurotransmittersinvitro.

GabapentinadministrationtoratsincreasesGABAturnoverinseveralbrainregionsinamannersimilartovalproate

sodium,althoughindifferentregionsofbrain.Therelevanceofthesevariousactionsofgabapentintothe

anticonvulsanteffectsremainstobeestablished.Inanimals,gabapentinreadilyentersthebrainandpreventsseizures

frommaximalelectroshock,fromchemicalconvulsantsincludinginhibitorsofGABAsynthesis,andingeneticmodels

ofseizures.

Aclinicaltrialofadjunctivetreatmentofpartialseizuresinpaediatricsubjects,ranginginagefrom3to12years,

showedanumericalbutnotstatisticallysignificantdifferenceinthe50%responderrateinfavourofthegabapentin

groupcomparedtoplacebo.Additionalpost-hocanalysesoftheresponderratesbyagedidnotrevealastatistically

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

thisadditionalpost-hocanalysisaresummarisedinthetablebelow:

*Themodifiedintenttotreatpopulationwasdefinedasallpatientsrandomisedtostudymedicationwhoalsohad

evaluableseizurediariesavailablefor28daysduringboththebaselineanddouble-blindphases.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,peakplasmagabapentinconcentrationsareobservedwithin2to3hours.

Gabapentinbioavailability(fractionofdoseabsorbed)tendstodecreasewithincreasingdose.Absolutebioavailability

ofa300mgcapsuleisapproximately60%.Food,includingahigh-fatdiet,hasnoclinicallysignificanteffecton

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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Gabapentinpharmacokineticsarenotaffectedbyrepeatedadministration.Althoughplasmagabapentinconcentrations

weregenerallybetween2µg/mland20µg/mlinclinicalstudies,suchconcentrationswerenotpredictiveofsafetyor

efficacy.PharmacokineticparametersaregiveninTable3.

Table3

Summaryofgabapentinmean(%CV)steady-statepharmacokineticparameters

followingeveryeighthoursadministration

=Maximumsteadystateplasmaconcentration

=TimeforCmax

T1/2=Eliminationhalf-life

AUC(0-8)=Steadystateareaunderplasmaconcentration-timecurvefromtime0

to8hourspostdose

Ae%=Percentofdoseexcretedunchangedintotheurinefromtime0to8hours

postdose

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

Pharmacokinetic

parameter 300mg 400mg 800mg

(N=7) (N=14) (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) 24.8 (24) 34.5 (34) 51.4 (27)

µghr/ml)

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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

(approximatelyfivetimesthemaximumdailyhumandoseonamg/m2ofbodysurfaceareabasis).

Teratogenesis

Gabapentindidnotincreasetheincidenceofmalformations,comparedtocontrols,intheoffspringofmice,rats,or

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

respectively,thehumandailydoseonamg/m2basis).

Gabapentininduceddelayedossificationintheskull,vertebrae,forelimbs,andhindlimbsinrodents,indicativeoffetal

growthretardation.Theseeffectsoccurredwhenpregnantmicereceivedoraldosesof1000or3000mg/kg/dayduring

organogenesisandinratsgiven500,1000,or2000mg/kgpriortoandduringmatingandthroughoutgestation.These

dosesareapproximately1to5timesthehumandoseof3600mgonamg/m2basis.

Noeffectswereobservedinpregnantmicegiven500mg/kg/day(approximately1/2ofthedailyhumandoseona

mg/m2basis).

Anincreasedincidenceofhydroureterand/orhydronephrosiswasobservedinratsgiven2000mg/kg/dayinafertility

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

perinatalandpostnatalstudy.Thesignificanceofthesefindingsisunknown,buttheyhavebeenassociatedwith

delayeddevelopment.Thesedosesarealsoapproximately1to5timesthehumandoseof3600mgonamg/m2basis.

Inateratologystudyinrabbits,anincreasedincidenceofpost-implantationfetalloss,occurredindosesgiven60,300,

and1500mg/kg/dayduringorganogenesis.Thesedosesareapproximately1/4to8timesthedailyhumandoseof3600

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Hydroxypropylcellulose

HydroxypropylcelluloseLH-21

HydrogenatedCastorOil

Sodiumlaurilsulfate

MagnesiumStearate

Carrageenan

Macrogol

Hydroxyethylcellulose

Maltodextrin

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C

6.5Natureandcontentsofcontainer

ThetabletsareavailableinPVC/Aluminiumblisterinpacksizesof10and100tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

RowexLtd.,

Bantry

Co.Cork

8MARKETINGAUTHORISATIONNUMBER

Irish Medicines Board

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation30 th

March2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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