GABAPENTIN TEVA

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0565/032/003
  • Authorization date:
  • 20-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GabapentinTeva400mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains400mggabapentin

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsules,hard

ProductimportedfromtheUK:

Hardgelatincapsuleswithaorangecapandbodyprintedwiththenumbers“93"and“40”andfilledwithawhitetooff

whitepowderwithsmallagglomerates.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Gabapentinisindicatedasadjunctivetherapyinthetreatmentofpartialseizureswithandwithoutsecondary

generalizationinadultsandchildrenaged6yearsandabove(seesection5.1).

Gabapentinisindicatedasmonotherapyinthetreatmentofpartialseizureswithandwithoutsecondarygeneralization

inadultsandadolescentsaged12yearsandabove.

Treatmentofperipheralneuropathicpain

Gabapentinisindicatedforthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-

herpeticneuralgiainadults.

4.2Posologyandmethodofadministration

Fororaluse.

Gabapentincanbegivenwithorwithoutfoodandshouldbeswallowedwholewithsufficientfluid-intake(e.g.aglass

ofwater).

ForallindicationsatitrationschemefortheinitiationoftherapyisdescribedinTable1,whichisrecommendedfor

adultsandadolescentsaged12yearsandabove.Dosinginstructionsforchildrenunder12yearsofageareprovided

underaseparatesub-headinglaterinthissection

Discontinuationofgabapentin

Inaccordancewithcurrentclinicalpractice,ifgabapentinhastobediscontinueditisrecommendedthisshouldbedone

graduallyoveraminimumof1weekindependentoftheindication. Table1

DOSINGCHART-INITIALTITRATION

Dayl Day2 Day3

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Epilepsy

Epilepsytypicallyrequireslong-termtherapy.Dosageisdeterminedbythetreatingphysicianaccordingtoindividual

toleranceandefficacy.

Adultsandadolescents:

Inclinicaltrials,theeffectivedosingrangewas900to3600mg/day.Therapymaybeinitiatedbytitratingthedoseas

describedinTable1orbyadministering300mgthreetimesaday(TID)onDay1.Thereafter,basedonindividual

patientresponseand.tolerability,thedosecanbefurtherincreasedin300mg/dayincrementsevery2-3daysuptoa

maximumdoseof3600mg/day.Slowertitrationofgabapentindosagemaybeappropriateforindividualpatients.The

minimumtimetoreachadoseof1800mg/dayisoneweek,toreach2400mg/dayisatotalof2weeks,andtoreach

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

clinicalstudies.Thetotaldailydoseshouldbedividedinthreesingledoses,themaximumtimeintervalbetweenthe

dosesshouldnotexceed12hourstopreventbreakthroughconvulsions.

Childrenaged6yearsandabove:

Thestartingdoseshouldrangefroml0to15mg/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).

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Useinpatientswithrenalimpairment

DosageadjustmentisrecommendedinpatientswithcompromisedrenalfunctionasdescribedinTable2and/orthose

undergoinghaemodialysis.Gabapentinl00mgcapsulescanbeusedtofollowdosingrecommendationsforpatientswith

renalinsufficiency.

Totaldailydoseshouldbeadministeredasthreedivideddoses.Reduceddosagesareforpatientswithrenalimpairment(creatinineclearance

<79ml/lmin).

Tobeadministeredas300everyotherday.

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

creatinineclearanceof7.5ml/minshouldreceiveone-halfthedailydosethatpatientswithacreatinineclearanceof15ml/minreceive).

Useinpatientsundergoinghaemodialysis

Foranuricpatientsundergoinghaemodialysiswhohaveneverreceivedgabapentin,aloadingdoseof300to400mg,

then200to300mgofgabapentinfollowingeach4hoursofhaemodialysis,isrecommended.Ondialysis-freedays,

thereshouldbenotreatmentwithgabapentin.

Forrenallyimpairedpatientsundergoinghaemodialysis,themaintenancedoseofgabapentinshouldbebasedonthe

dosingrecommendationsfoundinTable2.Inadditiontothemaintenancedose,anadditional200to300mgdose

followingeach4-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

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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Nosystematicstudiesinpatients65yearsorolderhavebeenconductedwithgabapentin.Inonedoubleblindstudyin

patientswithneuropathicpain,somnolence,peripheraloedemaandastheniaoccurredinasomewhathigherpercentage

inpatientsaged65yearsorabove,thaninyoungerpatients.Apartfromthesefindings,clinicalinvestigationsinthis

agegroupdonotindicateanadverseeventprofiledifferentfromthatobservedinyoungerpatients.

Theeffectsoflong-term(greaterthan36weeks)gabapentintherapyonlearning,intelligence,anddevelopmentin

childrenandadolescentshavenotbeenadequatelystudied.Thebenefitsofprolongedtherapymustthereforebe

weighedagainstthepotentialrisksofsuchtherapy.

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithanti-epilepticagentsinseveralindications.

Ameta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforgabapentin.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

Laboratorytests

Falsepositivereadingsmaybeobtainedinthesemi-quantitativedeterminationoftotalurineproteinbydipsticktests.It

isthereforerecommendedtoverifysuchapositivedipsticktestresultbymethodsbasedonadifferentanalytical

principlesuchastheBiuretmethod,turbidimetricordye-bindingmethods,ortousethesealternativemethodsfromthe

beginning.

300mg:Containssunsetyellow(E110)whichmayrarelycauseallergicreactions.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inastudyinvolvinghealthyvolunteers(N=12),whena60mgcontrolled-releasemorphinecapsulewasadministered2

hourspriortoa600mggabapentincapsule,meangabapentinAUCincreased.by44%comparedtogabapentin

administeredwithoutmorphine.Therefore,patientsshouldbecarefullyobservedforsignsofCNSdepression,suchas

somnolence,andthedoseofgabapentinormorphineshouldbereducedappropriately.

Nointeractionbetweengabapentinandphenobarbital,phenytoin,valproicacid,orcarbamazepinehasbeenobserved.

Gabapentinsteady-statepharmacokineticsaresimilarforhealthysubjectsandpatientswithepilepsyreceivingthese

antiepilepticagents.

Coadministrationofgabapentinwithoralcontraceptivescontainingnorethindroneand/orethinylestradiol,doesnot

influencethesteady-statepharmacokineticsofeithercomponent.

Coadministrationofgabapentinwithantacidscontainingaluminiumandmagnesium,reducesgabapentin

bioavailabilityupto24%.Itisrecommended.thatgabapentinbetakenattheearliesttwohoursfollowingantacid

administration

Renalexcretionofgabapentinisunalteredbyprobenecid.

Aslightdecreaseinrenalexcretionofgabapentinthatisobservedwhenitiscoadministeredwithcimetidineisnot

expectedtobeofclinicalimportance.

4.6Fertility,pregnancyandlactation

Riskrelatedtoepilepsyandantiepilepticmedicinalproductsingeneral

Theriskofbirthdefectsisincreasedbyafactorof2—3intheoffspringofmotherstreatedwithanantiepileptic

medicinalproduct.Mostfrequentlyreportedarecleftlip,cardiovascularmalformationsandneuraltubedefects.

Multipleantiepilepticdrugtherapymaybeassociatedwithahigherriskofcongenitalmalformationsthan

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Specialistadviceshouldbegiventowomenwhoarelikelytobecomepregnantorwhoareofchildbearingpotentialand

theneedforantiepileptictreatmentshouldbereviewedwhenawomanisplanningtobecomepregnant.Nosudden

discontinuationofantiepileptictherapyshouldbeundertakenasthismayleadtobreakthroughseizures,whichcould

haveseriousconsequencesforbothmotherandchild.Developmentaldelayinchildrenofmotherswithepilepsyhas

beenobservedrarely.Itisnotpossibletodifferentiateifthedevelopmentaldelayiscausedbygenetic,socialfactors,

maternalepilepsyortheantiepileptictherapy.

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,iftheywereonlyofmild

ormoderatedegree,theseundesirableeffectscouldbepotentiallydangerousinpatientsdrivingoroperatingmachinery.

Thisisespeciallytrueatthebeginningofthetreatmentandafterincreaseindose.

4.8Undesirableeffects

Theadversereactionsobservedduringclinicalstudiesconductedinepilepsy(adjunctiveandmonotherapy)and

neuropathicpainhavebeenprovidedinasinglelistbelowbyclassandfrequency(verycommon( ≥1/10),common(≥

1/100to<1/10),uncommon( ≥1/1000to<1/100);rare(≥1/10,000to<1/1,000);veryrare(<1/10,000).Wherean

adversereactionwasseenatdifferentfrequenciesinclinicalstudies,itwasassignedtothehighestfrequencyreported.

Additionalreactionsreportedfrompost-marketingexperienceareincludedasfrequencyNotknown(cannotbe

estimatedfromtheavailabledata)initalicsinthelistbelow.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Systemorganclass Adversedrugreactions

Infectionsandinfestations

VeryCommon:Viralinfection

Common: Pneumonia,respiratoryinfection,urinarytractinfection,infection,otitismedia

Bloodandlymphaticsystemdisorders

Common: leucopenia

Notknown: thrombocytopenia

Immunesystemdisorders

Uncommon: allergicreactions(e.g.urticaria)

Metabolismandnutritiondisorders

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Psychiatricdisorders

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

Notknown: hallucinations

Nervoussystemdisorders

VeryCommon:somnolence,dizziness,ataxia,

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

paraesthesia,hypaesthesia,coordinationabnormal,nystagmus,increased,decreased,orabsentreflexes

Uncommon: hypokinesia

Notknown: othermovementdisorders(e.g.choreoathetosis,dyskinesia,dystonia)

Eyedisorders

Common: visualdisturbancessuchasamblyopia,diplopia

Earandlabyrinthdisorders

Common: vertigo

Notknown: tinnitus

Cardiacdisorders

Uncommon: palpitations

Vasculardisorders

Common: hypertension,vasodilatation

Respiratory,thoracicandmediastinaldisorders

Common: dyspnoea,bronchitis,pharyngitis,cough,rhinitis

Gastrointestinaldisorders

Common: vomiting,nausea,dentalabnormalities,gingivitis,diarrhoea,abdominalpain,dyspepsia,constipation,

drymouthorthroat,flatulence

Notknown: pancreatitis

Hepatobiliarydisorders

Notknown: hepatitis,jaundice

Skinandsubcutaneoustissuedisorders

Common: facialoedema,purpuramostoftendescribedasbruisesresultingfromphysicaltrauma,rash,pruritus,

acne

Notknown: Stevens-Johnsonsyndrome,angioedema,erythemamultiforme,alopecia

Musculoskeletalandconnectivetissuedisorders

Common: arthralgia,myalgia,backpain,twitching

Notknown: myoclonus

Renalandurinarydisorders

Notknown: acuterenalfailure,incontinence

Reproductivesystemandbreastdisorders

Common: impotence

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Generaldisordersandadministrationsiteconditions

VeryCommon:fatigue,fever

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

Uncommon: generalizedoedema

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

unexplaineddeathshavebeenreportedwhereacausalrelationshiptotreatmentwithgabapentinhasnot

beenestablished.

Investigations

Common: WBC(whitebloodcellcount)decreased,weightgain

Uncommon: elevatedliverfunctiontests,SGOT(AST),SGPT(ALT)andbilirubin

Notknown: bloodglucosefluctuationsinpatientswithdiabetes

Injury,poisoningandproceduralcomplications

Common: accidentalinjury,fracture,abrasion

Undertreatmentwithgabapentincasesofacutepancreatitiswerereported.Causalitywithgabapentinisunclear(see

section4.4).

Inpatientsonhaemodialysisduetoend-stagerenalfailure,myopathywithelevatedcreatinekinaselevelshasbeen

reported.

Respiratorytractinfections,otitismedia,convulsionsandbronchitiswerereportedonlyinclinicalstudiesinchildren.

Additionally,inclinicalstudiesinchildren,aggressivebehaviourandhyperkinesiaswerereportedcommonly.

4.9Overdose

Acute,life-threateningtoxicityhasnotbeenobservedwithgabapentinoverdosesofupto49g.Symptomsofthe

overdosesincludeddizziness,doublevision,slurredspeech,drowsiness,lethargyandmilddiarrhoea.Allpatients

recoveredfullywithsupportivecare.Reducedabsorptionofgabapentinathigherdosesmaylimitdrugabsorptionat

thelimeofoverdosingand,hence,minimizetoxicityfromoverdoses.

Overdosesofgabapentin,particularlyincombinationwithotherCNSdepressantmedications,mayresultincoma.

Althoughgabapentincanberemovedbyhaemodialysis,basedonpriorexperienceitisusuallynotrequired.However,

inpatientswithsevererenalimpairment,haemodialysismaybeindicated.

Anorallethaldoseofgabapentinwasnotidentifiedinmiceandratsgivendosesashighas8000mg/kg.Signsofacute

toxicityinanimalsincludedataxia,labouredbreathing,ptosis,hypoactivity,orexcitation.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroups:OtherantiepilepticsATCcode:NO3AX12

Theprecisemechanismofactionofgabapentinisnotknown.

GabapentinisstructurallyrelatedtotheneurotransmitterGABA(gamma-aminobutyricacid)butitsmechanismof

actionisdifferentfromthatofseveralotheractivesubstancesthatinteractwithGABAsynapsesincludingvalproate,

barbiturates,benzodiazepines,GABAtransaminaseinhibitors,GABAuptakeinhibitors,GABAagonists,andGABA

prodrugs.Invitrostudieswithradiolabeledgabapentinhavecharacterizedanovelpeptidebindingsiteinratbrain

tissuesincludingneocortexandhippocampusthatmayrelatetoanticonvulsantandanalgesicactivityofgabapentinand

itsstructuralderivatives.Thebindingsiteforgabapentinhasbeenidentifiedasthealpha

-deltasubunitofvoltage-

gatedcalciumchannels.

Gabapentinatrelevantclinicalconcentrationsdoesnotbindtoothercommondrugorneurotransmitterreceptorsofthe

brainincludingGABA

,GABA

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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(agegroups3-5and.6-12years).Thedata

fromthisadditionalpost-hocanalysisaresummarised,inthetablebelow:

*Themodifiedintenttotreatpopulationwasdefinedasallpatientsrandomisedtostudymedicationwhoalsohad

evaluableseizurediariesavailablefor28daysduringboththebaselineanddouble-blindphases.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,peakplasmagabapentinconcentrationsareobservedwithin2to3hours.Gabapentin

bioavailability(fractionofdoseabsorbed)tendstodecreasewithincreasingdose.Absolutebioavailabilityofa300mg

capsuleisapproximately60%.Food,includingahigh-fatdiet,hasnoclinicallysignificanteffectongabapentin

pharmacokinetics.

Gabapentinpharmacokineticsarenotaffectedbyrepeatedadministration.Althoughplasmagabapentinconcentrations

weregenerallybetween2µg/mland20µg/mlinclinicalstudies,suchconcentrationswerenotpredictiveofsafetyor

efficacy.PharmacokineticparametersaregiveninTable3.

Table3

Summaryofgabapentinmean(%CV)steady-statepharmacokineticparameters

followingeveryeighthoursadministration

=Maximumsteadystateplasmaconcentration

=TimeforC

T1/2=Eliminationhalf-life

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

parameter 300mg

(N=7) 400 mg

(N=14) 800 mg

(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)

µg.hr/ml)

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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

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

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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/kgpriortoandduringmatingandthroughoutgestationThese

dosesareapproximately1to5timesthehumandoseof3600onamg/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

Capsules:

Talc

Pregelatinised(maize)starch

Capsulecap/body:

Gelatin

BlackIronOxide(E172)

RedIronOxide(E172)

YellowIronOxide(E172)

Titaniumdioxide(E171)

PrintingInk:

Shellac

Blackironoxide(E172)

Propyleneglycol

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/05/2011 CRN 2088853 page number: 10

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackage,keeptheblistersintheoutercarton.

6.5Natureandcontentsofcontainer

Blisterpacksof100capsulescontainedinanoverlabelledoutercardboardcarton.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

WPRHealthcareLtd

Unit10

AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA565/32/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20thMay2011

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/05/2011 CRN 2088853 page number: 11