GABAPENTIN PFIZER

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/056/002
  • Authorization date:
  • 23-09-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GabapentinPfizer300mgcapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsule,hardcontains300mgofgabapentin.

Excipients:

Each300mgcapsule,hardincludes41mglactosepercapsule.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

GabapentinPfizer300mgcapsules,hard:Whitetooff-whitepowderinasize#1(19.4mmlengthwithadiameter

body/capof6.63mm/6.91mm),hardgelatincapsulewithayellowopaquebodyandcap.CapsuleisimprintedwithG

and5027inblueink.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Gabapentinisindicatedasadjunctivetherapyinthetreatmentofpartialseizureswithandwithoutsecondary

generalizationinadultsandchildrenaged6yearsandabove(seesection5.1).

Gabapentinisindicatedasmonotherapyinthetreatmentofpartialseizureswithandwithoutsecondarygeneralization

inadultsandadolescentsaged12yearsandabove.

Treatmentofperipheralneuropathicpain

Gabapentinisindicatedforthetreatmentofperipheralneuropathicpainsuchaspainfuldiabeticneuropathyandpost-

herpeticneuralgiainadults.

4.2Posologyandmethodofadministration

ForallindicationsatitrationschemefortheinitiationoftherapyisdescribedinTable1,whichisrecommendedfor

adultsandadolescentsaged12yearsandabove.Dosinginstructionsforchildrenunder12yearsofageareprovided

underaseparatesub-headinglaterinthissection.

Discontinuationofgabapentin

Inaccordancewithcurrentclinicalpractice,ifgabapentinhastobediscontinueditisrecommendedthisshouldbedone

graduallyoveraminimumof1weekindependentoftheindication. Table1

DOSINGCHART–INITIALTITRATION

Day1 Day2 Day3

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Epilepsy

Epilepsytypicallyrequireslong-termtherapy.Dosageisdeterminedbythetreatingphysicianaccordingtoindividual

toleranceandefficacy.

Adultsandadolescents:

Inclinicaltrials,theeffectivedosingrangewas900to3600mg/day.Therapymaybeinitiatedbytitratingthedoseas

describedinTable1orbyadministering300mgthreetimesaday(TID)onDay1.Thereafter,basedonindividualpatient

responseandtolerability,thedosecanbefurtherincreasedin300mg/dayincrementsevery2-3daysuptoamaximum

doseof3600mg/day.Slowertitrationofgabapentindosagemaybeappropriateforindividualpatients.Theminimum

timetoreachadoseof1800mg/dayisoneweek,toreach2400mg/dayisatotalof2weeks,andtoreach3600mg/day

isatotalof3weeks.Dosagesupto4800mg/dayhavebeenwelltoleratedinlong-termopen-labelclinicalstudies.The

totaldailydoseshouldbedividedinthreesingledoses,themaximumtimeintervalbetweenthedosesshouldnotexceed

12hourstopreventbreakthroughconvulsions.

Childrenaged6yearsandabove:

Thestartingdoseshouldrangefrom10to15mg/kg/dayandtheeffectivedoseisreachedbyupwardtitrationovera

periodofapproximatelythreedays.Theeffectivedoseofgabapentininchildrenaged6yearsandolderis25to35

mg/kg/day.Dosagesupto50mg/kg/dayhavebeenwelltoleratedinalong-termclinicalstudy.Thetotaldailydose

shouldbedividedinthreesingledoses,themaximumtimeintervalbetweendosesshouldnotexceed12hours.

Itisnotnecessarytomonitorgabapentinplasmaconcentrationstooptimizegabapentintherapy.Further,gabapentinmay

beusedincombinationwithotherantiepilepticmedicinalproductswithoutconcernforalterationoftheplasma

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.Gabapentin100mgcapsulescanbeusedtofollowdosingrecommendationsforpatientswith

renalinsufficiency.

Totaldailydoseshouldbeadministeredasthreedivideddoses.Reduceddosagesareforpatientswithrenalimpairment

(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.

Methodofadministration

Fororaluse.

Gabapentincanbegivenwithorwithoutfoodandshouldbeswallowedwholewithsufficientfluid-intake(e.g.aglass

ofwater).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithanti-epilepticagentsinseveralindications.

Ameta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforgabapentin

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

Ifapatientdevelopsacutepancreatitisundertreatmentwithgabapentin,discontinuationofgabapentinshouldbe

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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Althoughthereisnoevidenceofreboundseizureswithgabapentin,abruptwithdrawalofanticonvulsantsinepileptic

patientsmayprecipitatestatusepilepticus(seesection4.2).

Aswithotherantiepilepticmedicinalproducts,somepatientsmayexperienceanincreaseinseizurefrequencyorthe

onsetofnewtypesofseizureswithgabapentin.

Aswithotheranti-epileptics,attemptstowithdrawconcomitantanti-epilepticsintreatmentrefractivepatientsonmore

thanoneanti-epileptic,inordertoreachgabapentinmonotherapyhavealowsuccessrate.

Gabapentinisnotconsideredeffectiveagainstprimarygeneralizedseizuressuchasabsencesandmayaggravatethese

seizuresinsomepatients.Therefore,gabapentinshouldbeusedwithcautioninpatientswithmixedseizuresincluding

absences.

Nosystematicstudiesinpatients65yearsorolderhavebeenconductedwithgabapentin.Inonedoubleblindstudyin

patientswithneuropathicpain,somnolence,peripheraloedemaandastheniaoccurredinasomewhathigherpercentage

inpatientsaged65yearsorabove,thaninyoungerpatients.Apartfromthesefindings,clinicalinvestigationsinthis

agegroupdonotindicateanadverseeventprofiledifferentfromthatobservedinyoungerpatients.

Theeffectsoflong-term(greaterthan36weeks)gabapentintherapyonlearning,intelligence,anddevelopmentin

childrenandadolescentshavenotbeenadequatelystudied.Thebenefitsofprolongedtherapymustthereforebe

weighedagainstthepotentialrisksofsuchtherapy.

DrugRashwithEosinophiliaandSystemicSymptoms(DRESS)

Severe,life-threatening,systemichypersensitivityreactionssuchasDrugrashwitheosinophiliaandsystemic

symptoms(DRESS)havebeenreportedinpatientstakingantiepilepticdrugsincludinggabapentin.

Itisimportanttonotethatearlymanifestationsofhypersensitivity,suchasfeverorlymphadenopathy,maybepresent

eventhoughrashisnotevident.Ifsuchsignsorsymptomsarepresent,thepatientshouldbeevaluatedimmediately.

Gabapentinshouldbediscontinuedifanalternativeetiologyforthesignsorsymptomscannotbeestablished.

Laboratorytests

Falsepositivereadingsmaybeobtainedinthesemi-quantitativedeterminationoftotalurineproteinbydipsticktests.It

isthereforerecommendedtoverifysuchapositivedipsticktestresultbymethodsbasedonadifferentanalytical

principlesuchastheBiuretmethod,turbidimetricordye-bindingmethods,ortousethesealternativemethodsfromthe

beginning.

GabapentinPfizercapsules,hardcontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,the

Lapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

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

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Coadministrationofgabapentinwithantacidscontainingaluminiumandmagnesium,reducesgabapentinbioavailabilityup

to24%.Itisrecommendedthatgabapentinbetakenattheearliesttwohoursfollowingantacidadministration.

Renalexcretionofgabapentinisunalteredbyprobenecid.

Aslightdecreaseinrenalexcretionofgabapentinthatisobservedwhenitiscoadministeredwithcimetidineisnot

expectedtobeofclinicalimportance.

4.6Fertility,pregnancyandlactation

Riskrelatedtoepilepsyandantiepilepticmedicinalproductsingeneral

Theriskofbirthdefectsisincreasedbyafactorof2–3intheoffspringofmotherstreatedwithanantiepileptic

medicinalproduct.Mostfrequentlyreportedarecleftlip,cardiovascularmalformationsandneuraltubedefects.

Multipleantiepilepticdrugtherapymaybeassociatedwithahigherriskofcongenitalmalformationsthan

monotherapy,thereforeitisimportantthatmonotherapyispractisedwheneverpossible.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.Gabapentinactsonthe

centralnervoussystemandmaycausedrowsiness,dizzinessorotherrelatedsymptoms.Even,iftheywereonlyofmild

ormoderatedegree,theseundesirableeffectscouldbepotentiallydangerousinpatientsdrivingoroperatingmachinery.

Thisisespeciallytrueatthebeginningofthetreatmentandafterincreaseindose.

4.8Undesirableeffects

Theadversereactionsobservedduringclinicalstudiesconductedinepilepsy(adjunctiveandmonotherapy)and

neuropathicpainhavebeenprovidedinasinglelistbelowbyclassandfrequencyverycommon(1/10);common(

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

adversereactionwasseenatdifferentfrequenciesinclinicalstudies,itwasassignedtothehighestfrequencyreported.

Additionalreactionsreportedfrompost-marketingexperienceareincludedasfrequencyNotknown(cannotbe

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Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

BodySystem Adversedrugreactions

Infectionsandinfestations

VeryCommon Viralinfection

Common Pneumonia,respiratoryinfection,urinarytractinfection,

infection,otitismedia

Bloodandthelymphaticsystemdisorders

Common leucopenia

Notknown thrombocytopenia

Immunesystemdisorders

Uncommon

Notknown allergicreactions(e.g.urticaria)

hypersensitivitysyndrome,asystemicreactionwithavariable

presentationthatcanincludefever,rash,hepatitis,

lymphadenopathy,eosinophilia,andsometimesothersigns

andsymptoms

MetabolismandNutritionDisorders

Common anorexia,increasedappetite

Psychiatricdisorders

Common hostility,confusionandemotionallability,depression,

anxiety,nervousness,thinkingabnormal

Notknown hallucinations

Nervoussystemdisorders

VeryCommon somnolence,dizziness,ataxia

Common

Uncommon convulsions,hyperkinesias,dysarthria,amnesia,tremor,

insomnia,headache,sensationssuchasparesthesia,

hypaesthesia,coordinationabnormal,nystagmus,increased,

decreased,orabsentreflexes

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,diarrhea,

abdominalpain,dyspepsia,constipation,drymouthorthroat,

flatulence

Notknown pancreatitis

Hepatobiliarydisorders

Notknown hepatitis,jaundice

Skinandsubcutaneoustissuedisorders

Common facialoedema,purpuramostoftendescribedasbruises

resultingfromphysicaltrauma,rash,pruritus,acne

Notknown Stevens-Johnsonsyndrome,angioedema,erythema

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Undertreatmentwithgabapentincasesofacutepancreatitiswerereported.Causalitywithgabapentinisunclear(see

section4.4).

Inpatientsonhaemodialysisduetoend-stagerenalfailure,myopathywithelevatedcreatinekinaselevelshasbeen

reported.

Respiratorytractinfections,otitismedia,convulsionsandbronchitiswerereportedonlyinclinicalstudiesinchildren.

Additionally,inclinicalstudiesinchildren,aggressivebehaviourandhyperkinesiaswerereportedcommonly.

4.9Overdose

Acute,life-threateningtoxicityhasnotbeenobservedwithgabapentinoverdosesofupto49g.Symptomsoftheoverdoses

includeddizziness,doublevision,slurredspeech,drowsiness,lethargyandmilddiarrhoea.Allpatientsrecoveredfullywith

supportivecare.Reducedabsorptionofgabapentinathigherdosesmaylimitdrugabsorptionatthetimeofoverdosingand,

hence,minimizetoxicityfromoverdoses.

Overdosesofgabapentin,particularlyincombinationwithotherCNSdepressantmedications,mayresultincoma

Althoughgabapentincanberemovedbyhaemodialysis,basedonpriorexperienceitisusuallynotrequired.However,

inpatientswithsevererenalimpairment,haemodialysismaybeindicated.

Anorallethaldoseofgabapentinwasnotidentifiedinmiceandratsgivendosesashighas8000mg/kg.Signsofacute

toxicityinanimalsincludedataxia,labouredbreathing,ptosis,hypoactivity,orexcitation.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

systemicsymptoms

Musculoskeletalandconnectivetissuedisorders

Common arthralgia,myalgia,backpain,twitching

Notknown myoclonus

Renalandurinarydisorder

Notknown acuterenalfailure,incontinence

Reproductivesystemandbreastdisorders

Common impotence

Notknown breasthypertrophy,gynaecomastia

Generaldisordersandadministrationsiteconditions

VeryCommon fatigue,fever

Common peripheraloedema,abnormalgait,asthenia,pain,malaise,flu

syndrome

Uncommon

Notknown generalizedoedema

withdrawalreactions(mostlyanxiety,insomnia,nausea,

pains,sweating),chestpain.Suddenunexplaineddeathshave

beenreportedwhereacausalrelationshiptotreatmentwith

gabapentinhasnotbeenestablished.

Investigations

Common

Uncommon WBC(whitebloodcellcount)decreased,weightgain

elevatedliverfunctiontestsSGOT(AST),SGPT(ALT)and

bilirubin

Notknown bloodglucosefluctuationsinpatientswithdiabetes

Injury,poisoningandproceduralcomplications

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Theprecisemechanismofactionofgabapentinisnotknown.

GabapentinisstructurallyrelatedtotheneurotransmitterGABA(gamma-aminobutyricacid)butitsmechanismofactionis

differentfromthatofseveralotheractivesubstancesthatinteractwithGABAsynapsesincludingvalproate,barbiturates,

benzodiazepines,GABAtransaminaseinhibitors,GABAuptakeinhibitors,GABAagonists,andGABAprodrugs.Invitro

studieswithradiolabeledgabapentinhavecharacterizedanovelpeptidebindingsiteinratbraintissuesincludingneocortex

andhippocampusthatmayrelatetoanticonvulsantandanalgesicactivityofgabapentinanditsstructuralderivatives.The

bindingsiteforgabapentinhasbeenidentifiedasthealpha

-deltasubunitofvoltage-gatedcalciumchannels.

Gabapentinatrelevantclinicalconcentrationsdoesnotbindtoothercommondrugorneurotransmitterreceptorsofthe

brainincludingGABA

,GABA

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

Gabapentindoesnotinteractwithsodiumchannelsinvitroandsodiffersfromphenytoinandcarbamazepine.Gabapentin

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

atconcentrationsgreaterthan100 µ

M,whicharenotachievedinvivo.Gabapentinslightlyreducesthereleaseof

monoamineneurotransmittersinvitro.GabapentinadministrationtoratsincreasesGABAturnoverinseveralbrainregions

inamannersimilartovalproatesodium,althoughindifferentregionsofbrain.Therelevanceofthesevariousactionsof

gabapentintotheanticonvulsanteffectsremainstobeestablished.Inanimals,gabapentinreadilyentersthebrainand

preventsseizuresfrommaximalelectroshock,fromchemicalconvulsantsincludinginhibitorsofGABAsynthesis,andin

geneticmodelsofseizures.

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

weregenerallybetween2µg/mland20µg/mlinclinicalstudies,suchconcentrationswerenotpredictiveofsafetyor

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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Table3

Summaryofgabapentinmean(%CV)steady-statepharmacokineticparametersfollowingevery

eighthoursadministration

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

Pharmacokinetic

parameter 300mg

(N=7) 400mg

(N=14) 800mg

(N=14)

Mean %CV Mean %CV Mean %CV

(µg/ml) 4.02 (24) 5.74 (38) 8.71 (29)

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

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

AUC(0-8)

µghr/ml) 24.8 (24) 34.5 (34) 51.4 (27)

Ae%(%) NA NA 47.2 (25) 34.4 (37)

=Maximumsteadystateplasmaconcentration

=TimeforC

T1/2=Eliminationhalf-life

AUC(0-8)=Steadystateareaunderplasmaconcentration-timecurvefrom

time0to8hourspostdose

Ae%=Percentofdoseexcretedunchangedintotheurinefromtime0to8

hourspostdose

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5.3Preclinicalsafetydata

Carcinogenesis

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

fortwoyears.Astatisticallysignificantincreaseintheincidenceofpancreaticacinarcelltumorswasfoundonlyin

maleratsatthehighestdose.Peakplasmadrugconcentrationsinratsat2000mg/kg/dayare10timeshigherthan

plasmaconcentrationsinhumansgiven3600mg/day.Thepancreaticacinarcelltumorsinmaleratsarelow-grade

malignancies,didnotaffectsurvival,didnotmetastasizeorinvadesurroundingtissue,andweresimilartothoseseenin

concurrentcontrols.Therelevanceofthesepancreaticacinarcelltumorsinmaleratstocarcinogenicriskinhumansis

unclear.

Mutagenesis

Gabapentindemonstratednogenotoxicpotential.Itwasnotmutagenicinvitroinstandardassaysusingbacterialor

mammaliancells.Gabapentindidnotinducestructuralchromosomeaberrationsinmammaliancellsinvitroorinvivo,

anddidnotinducemicronucleusformationinthebonemarrowofhamsters.

ImpairmentofFertility

Noadverseeffectsonfertilityorreproductionwereobservedinratsatdosesupto2000mg/kg(approximatelyfivetimes

themaximumdailyhumandoseonamg/m 2

ofbodysurfaceareabasis).

Teratogenesis

Gabapentindidnotincreasetheincidenceofmalformations,comparedtocontrols,intheoffspringofmice,rats,orrabbits

atdosesupto50,30and25timesrespectively,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(approximately1/2ofthedailyhumandoseonamg/m 2

basis).

Anincreasedincidenceofhydroureterand/orhydronephrosiswasobservedinratsgiven2000mg/kg/dayinafertilityand

generalreproductionstudy,1500mg/kg/dayinateratologystudy,and500,1000,and2000mg/kg/dayinaperinataland

postnatalstudy.Thesignificanceofthesefindingsisunknown,buttheyhavebeenassociatedwithdelayeddevelopment.

Thesedosesarealsoapproximately1to5timesthehumandoseof3600mgonamg/m 2

basis.

Inateratologystudyinrabbits,anincreasedincidenceofpost-implantationfetalloss,occurredindosesgiven60,300,and

1500mg/kg/dayduringorganogenesis.Thesedosesareapproximately1/4to8timesthedailyhumandoseof3600mgon

amg/m 2

basis.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontent:

lactosemonohydrate

maizestarch

Irish Medicines Board

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Date Printed 27/09/2011 CRN 2081697 page number: 10

Capsuleshell300mg:

gelatin

sodiumlaurilsulfate.

titaniumdioxide(E171)

yellowironoxide(E172)

Printingink:

shellac

titaniumdioxide(E171)

indigocarminealuminiumsalt(E132)

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove30°C

6.5Natureandcontentsofcontainer

PVC/PVDC/aluminiumfoilblisters

Suppliedinpacksof20,30,50,60,84,90,98,100,200,500,1000capsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/56/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23September2011

Irish Medicines Board

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Date Printed 27/09/2011 CRN 2081697 page number: 11

Irish Medicines Board

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Date Printed 27/09/2011 CRN 2081697 page number: 12