GABTURE

Main information

  • Trade name:
  • GABTURE Capsule 400 Milligram
  • Dosage:
  • 400 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GABTURE Capsule 400 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1050/001/003
  • Authorization date:
  • 18-11-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1050/001/003

CaseNo:2062962

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

MilpharmLimited

Ares,OdysseyBusinessPark,WestEndRoad,SouthRuislipHA46QD,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gabture400mgCapsules

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom12/03/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gabture400mgCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Gabapentin400mg.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

Size'0'orange/orangehardgelatincapsulemarked'MG400'.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Monotherapyinadultsandchildrenover12yearsofage

Gabapentinisusedasanantiepilepticindicatedformonotherapyoradd-ontreatmentforadultsandchildrenover12

yearsofagewithpartialseizuresorpartialseizureswithsecondarygeneralisation,includingpatientswithnewly

diagnosedseizures.

Monotherapyinchildrenunder12yearsofageisnotrecommendeduntilfurtherinformationisavailablefrom

controlledtrialsinthisparticularagegroup.

Add-ontherapyinadultsandchildrenage3yearsandabove

Gabapentinisusedasanantiepilepticindicatedforadd-ontreatmentforpartialseizuresorpartialseizureswith

secondarygeneralisationinadultsandchildrenage3yearsandabovewhohavenotattainedsatisfactorycontrolorwho

areintolerantwithstandardanticonvulsantseitherusedaloneorincombination.

Forchildrenaged3yearsandabove,Gabapentinshouldbeinitiatedandsupervisedbyaneurologicalspecialist.

NeuropathicPain

GabapentinCombixisindicatedforthetreatmentofneuropathicpain.

4.2Posologyandmethodofadministration

AdultsandChildrenagedover12yearsofage

TheeffectivedoseofGabapentinis900-3600mg/day.

ThenormalstartingdoseofGabapentinasmonotherapyfornewlydiagnosedpatientsis900mg/day.

Titrationtoaneffectivedosecanprogressrapidlyandcanbeachievedoverafewdaysbyadministering300mgoncea

dayonDay1,300mgtwiceadayonDay2and300mgthreetimesadayonDay3.Afterwards,thedosecanbe

increasedto1200mgperdaygiveninthreeequallydivideddoses,andifnecessary,furthertitrationtoamaximumof

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Themaximumtimebetweendosesinathreetimesdailyscheduleshouldnotexceed12hours.

ElderlyandPatientswithCompromisedRenalFunction

Elderlypatientsmayneeddosageadjustmentduetodeclineofrenalfunction.Itisrecommendedthatpatientswith

compromisedrenalfunctionhavetheirdosageadjusted(seeTable1)

Table1:MaintenancedosageofGabapentininadultswithreducedrenalfunction

Totaldailydoseshouldbeadministeredthreetimesdaily.

Tobeadministeredas300mgeveryotherday.

PatientsonHaemodialysis

ForpatientsundergoinghaemodialysiswhohaveneverreceivedGabapentin,aloadingdoseof300mgto400mgis

recommended,then200to300mgGabapentinfollowingeach4hoursofhaemodialysis.

Children3-12yearsofage

TheeffectivedoseofGabapentinis25to35mg/kg/daygivenindivideddoses(3timesaday).Titrationtoaneffective

dosecantakeplaceover3daysbygiving10mg/kg/dayonDay1,20mg/kg/dayonDay2and25to35mg/kg/dayon

Day3.Inalong-termclinicalstudy,dosagesupto40to50mg/kg/dayhavebeenwelltolerated.Dosesof60

mg/kg/dayhavealsobeenadministeredtoanumberofsmallchildren.

Thefollowingmaintenancedosingscheduleissuggested:

Insufficientevidencewasavailablefromappropriatestudiesuponwhichtobasedosagerecommendationsfor

monotherapyuseinchildrenundertheageof12years.

Itisnotnecessarytomonitorgabapentinplasmaconcentrationstooptimisegabapentintherapy.Ifgabapentinistobe

discontinuedand/oranalternateanticonvulsantmedicationisaddedtothetreatment,itshouldbeprogressedgradually

overaminimumofoneweek.

NeuropathicPain

Adults(overtheageof18)

Gabapentinshouldbetitratedtoamaximumdoseof1800mgperday.

Titrationtoaneffectivedosecanprogressrapidlyandcanbeaccomplishedoverafewdaysbyadministering300mg

onceadayonday1,300mgtwiceadayonday2and300mgthreetimesadayonday3.Thereafter,thedosecanbe

increasedusingincrementsof300mgperdaygiveninthreeequallydivideddosestoamaximumof1800mgperday.

ItisnotnecessarytomonitorgabapentinplasmaconcentrationstooptimiseGabapentintherapy.

Themaximumtimebetweendosesinathreetimesdailyscheduleshouldnotexceed12hours.Gabapentinmaybe

RenalFunctionCreatinineClearance(ml/min)

TotalDailyDose(mg/day)Range a

≥80 900-3600mg

50-79 600-1800mg

30-49 300-900mg

15-29

-600mg

<15 150 b

-300mg

WeightRange(kg) TotalDose(mg/day)

17-25 600

26-36 900

37-50 1200

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Elderly

Elderlypatientsmayrequiredosageadjustmentbecauseofdecliningrenalfunctionwithage(seeTable1).

Patientswithcompromisedrenalfunctionorthoseundergoinghaemodialysis

Dosageadjustmentisrecommendedinpatientswithcompromisedrenalfunctionorthoseundergoinghaemodialysis.

Table1:MaintenancedosageofGabapentininadultswithreducedrenalfunction

Totaldailydoseshouldbeadministeredasatidregimen.Dosesusedtotreatpatientswithnormalrenalfunction

(creatinineclearance>80ml/min)rangefrom900to2400mg/day.Reduceddosagesareforpatientswithrenal

impairment(creatinineclearance<79ml/min).

Tobeadministeredas300mgeveryotherday.

Forpatientsundergoinghaemodialysiswhohaveneverreceivedgabapentin,aloadingdoseof300to400mgis

recommendedthen200to300mgofgabapentinfollowingeach4hoursofhaemodialysis.

4.3Contraindications

Gabapentiniscontraindicatedinpatientswhohaveshownhypersensitivitytoanyoftheconstituents.

4.4Specialwarningsandprecautionsforuse

Abruptwithdrawalofanticonvulsantagentsinepilepticpatientsmayprecipitatestatusepilepticusalthough,todate,

therehavebeennoreportedcasesofreboundseizureswithgabapentin.Dosereduction,discontinuationorsubstitution

ofalternativeanticonvulsantmedicationshouldbedonegraduallyoveraminimumofoneweekatthediscretionofthe

clinician.

Generally,gabapentinisnotconsideredeffectiveinthetreatmentofabsenceseizures.

Patientswithepilepsycanbethesubjectofmoodandbehaviouraldisturbances.Althoughthesehavebeennotedin

patientsongabapentin,acausallinkhasnotbeenestablished.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nointeractionwasobservedbetweengabapentinandphenytoin,valproicacid,carbamazepineorphenobarbital.

Steady-statepharmacokineticsofgabapentinaresimilarforhealthysubjectsandpatientswithepilepsyreceiving

antiepilepticagents.

Administrationofgabapentinwithoralcontraceptivesincludingnorethindroneand/orethinyloestradiolpresentsno

influenceonthesteady-statepharmacokineticsofeithercomponent.

Co-administrationofantacidscontainingaluminiumandmagnesiumreducesthebioavailabilityofgabapentinupto

Renalfunction

CreatinineClearance

(ml/minute) TotalDailyDose a

(mg/day)

NORMALDOSAGE

≥80

1200 2400

50-79 600 600 1200

30-49 300 300 600

15-29 150 b

<15 150 b

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Renalexcretionofgabapentinisnotalteredbyprobenecid.Aslightdecreaseinrenalexcretionofgabapentin,thatis

observedwhenco-administeredwithcimetidine,isofnosignificantclinicalimportance.Fooddoesnotalterthe

pharmacokineticsofgabapentin.

FalsepositivereadingswerereportedwiththeAmesN-MultistixSGdipsticktestwhengabapentinorplacebowere

addedtootheranticonvulsantdrugs.Inthiscase,themorespecificsulphosalicylicacidprecipitationmethodis

recommendedtodetermineurinaryprotein.

4.6Pregnancyandlactation

Thesafeuseofgabapentininhumanpregnancyhasnotbeenestablished.Reproductionstudiesinmiceatdosesupto

42times,inratsatdosesupto28timesandinrabbitsatdosesupto21timesthehumandosehaveshownnocasesof

impairedfertilityorharmtothefoetus.However,asanimalreproductionstudiesarenotalwayspredictiveofhuman

response,administrationofgabapentinshouldonlyberecommendedinpregnancyifclearlyneeded.

Itisunclearwhethergabapentinisexcretedinhumanmilk.Howeverasmanydrugsareexcretedinhumanmilk,there

canbepotentialforseriousadversereactionsfromgabapentininnursinginfants.Adecisionshouldthereforebemade

toeitherdiscontinuenursingortodiscontinuethedrug,takingintoaccounttheimportanceofgabapentintothemother.

4.7Effectsonabilitytodriveandusemachines

Likeallanticonvulsants,themodeofactionofgabapentinisonthecentralnervoussystem.Drowsiness,dizziness,or

otherrelatedsymptomsmayoccuruponadministrationofgabapentin.Theseincidents,althoughmildormoderate,

maybedangerousinpatientsdrivingoroperatingmachinery,particularlyuntilwhentheindividualpatient’s

experiencewiththedrugisestablished.

4.8Undesirableeffects

Gabapentinhasbeenevaluatedforsafetyinmorethan2000patientsandwaswelltolerated.

IncidenceinAdd-onControlledClinicalTrials

Table2liststreatment-emergentsignsandsymptomsthatoccurredinatleast1%ofpatientswithpartialseizures

during12-weekcontrolledstudiescomparinggabapentinwithplacebo.Inthesestudies,eithergabapentinorplacebo

wasaddedtothepatient'scurrentantiepilepticdrugtherapy.

Adverseevents,obtainedfrompooleddatafromfivemulticentrestudies,wereusuallyreportedasmildtomoderate

(66%ofpatients)withamediantimetoresolutionoftwoweeks.

Table2:SummaryofTreatmentEmergentSignsandSymptomsin1%ofGabapentinTreatedPatientsin

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[Number(Percent)ofPatients]

AdverseEvent(AE) Gabapentin

N=543 Placebo

N=378

Somnolence 105(19.3) 33(8.7)

Dizziness 93(17.1) 26(6.9)

Ataxia 68(12.5) 21(5.6)

Fatigue 60(11.0) 19(5.0)

Nystagmus 45(8.3) 15(4.0)

Headache 44(8.1) 34(9.0)

Tremor 37(6.8) 12(3.2)

Nauseaand/orvomiting 33(6.1) 27(7.1)

Diplopia 32(5.9) 7(1.9)

Amblyopia 23(4.2) 4(1.1)

Rhinitis 22(4.1) 14(3.7)

WeightIncrease 16(2.9) 6(1.6)

Pharyngitis 15(2.8) 6(1.6)

Dysarthria 13(2.4) 2(0.5)

Nervousness 13(2.4) 7(1.9)

Dyspepsia 12(2.2) 2(0.5)

Amnesia 12(2.2) 0(0.0)

Myalgia 11(2.0) 7(1.9)

Coughing 10(1.8) 5(1.3)

AbdominalPain 10(1.8) 9(2.4)

BackPain 10(1.8) 2(0.5)

Depression 10(1.8) 7(1.8)

ThinkingAbnormal 9(1.7) 5(1.3)

MouthorThroatDry 9(1.7) 2(0.5)

PeripheralOedema 9(1.7) 2(0.5)

Confusion 9(1.7) 7(1.9)

Constipation 8(1.5) 3(0.8)

Impotence 8(1.5) 4(1.1)

DentalAbnormalities 8(1.5) 1(0.3)

Rash 8(1.5) 6(1.6)

Diarrhoea 7(1.3) 8(2.1)

ViralInfection 7(1.3) 8(2.1)

Fever 7(1.3) 5(1.3)

Twitching 7(1.3) 2(0.5)

Abrasion 7(1.3) 0(0.0)

Pruritus 7(1.3) 2(0.5)

IncreasedAppetite 6(1.1) 3(0.8)

WBCDecreased 6(1.1) 2(0.5)

Insomnia 6(1.1) 7(1.9)

Acne 6(1.1) 5(1.3)

Fracture 6(1.1) 3(0.8)

Vasodilatation 6(1.1) 1(0.3)

Leukopenia 6(1.1) 2(0.5)

CoordinationAbnormal 6(1.1) 1(0.3)

EmotionalLability 6(1.1) 5(1.3)

COSTARTpreferredterm

Plusbackgroundantiepilepticdrugtherapy

a b b

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Thoseeventsthatoccurredinatleast1%ofthestudyparticipantswithepilepsywhoreceivedgabapentinasadd-on

therapyinanyclinicalstudyandthatarenotdescribedintheprevioussectionaresummarisedbelow.

BodyAsAWhole:asthenia,malaise,facialoedema

Cardiovascularsystem:hypertension

DigestiveSystem:flatulence,anorexia,gingivitis

HaemicandLymphaticSystems:purpuramostoftendescribedasbruisesresultingfromphysicaltrauma

MusculoskeletalSystem:arthralgia

NervousSystem:vertigo,hyperkinesia,increased,decreasedorabsentreflexes,paraesthesia,anxiety,hostility

RespiratorySystem:pneumonia

UrogenitalSystem:urinarytractinfection

SpecialSenses:abnormalvisionmostoftendescribedasavisualdisturbance

Thesideeffectreportedindosecontrolledmonotherapystudieswassimilartothatinadd-onstudies.

Post-marketingsurveillance

Aswiththeotherantiepilepticdrugs,therehavebeenrarereportsofpancreatitis,elevatedliverfunctiontests,erythema

multiforme,StevensJohnsonSyndromeandsuddenunexplaineddeathswhereacausalrelationshiptotreatmenthas

notbeenestablished.

Children

Sideeffectsthatoccurredinchildrenaged3-12years,withanincidenceof2%orgreaterthanplaceboincontrolled

add-ontrials,were:somnolence,fatigue,weightincrease,hostility,emotionallability,dizziness,hyperkinesia,

nausea/vomiting,viralinfection,fever,bronchitis,respiratoryinfection.Someofthesesideeffectsmaybeattributedto

commonviralchildhoodillness.

4.9Overdose

Inlimitedexperiencewithoverdoses,thefollowinghavebeennoted:dizziness,doublevisionandslurredspeech.

OverdosesofGabapentin,upto30gingestedatonetime,havebeenreported.Symptomsweredrowsinessandmild

diarrhoeabutwithafullrecovery.Therefore,acute,life-threateningtoxicityhasnotbeenobservedwithGabapentin

overdosesofupto30gperday.ReducedabsorptionofGabapentinathigherdosesmaylimitdrugabsorptionatthe

timeofoverdosingand,hence,toxicityfromoverdoses.

AlthoughGabapentincanberemovedbyhaemodialysisitisnotusuallyrequired.However,inpatientswithrenal

impairment,haemodialysismaybeindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Gabapentinisananticonvulsantstructurallyrelatedtotheneurotransmittergamma-aminobutyricacid(GABA)butits

mechanismofactionisdifferentfromthatofseveraldrugsthatinteractwithGABAsynapses.Theidentificationand

functionofthegabapentinbindingsiteremainstobeelucidatedandthesignificanceofitsvariousactionstothe

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5.2Pharmacokineticproperties

FollowingsingleoraldosesofGabapentin,regardlessofdosesizeorformulation,themeanplasmagabapentin

concentrations(C

)occurredapproximately3hours(T

).FollowingmultipledoseadministrationthemeanT

valueswereapproximately1hourshorterthanthevaluesfollowingsingle-doseadministration.

Atdosesof300-4800mg,meanC

andAUCvaluesincreasedwithincreasingdose,however,theincreasewasless

thandoseproportional.

FollowingrepeatedGabapentinadministration,steady-statewasachievedwithin1to2daysafterthestartofthe

multipledosingandwasmaintainedthroughoutthedosingregime.

Followingsingle-doseadministrationsof300and400mgofgabapentin,theplasmagabapentinconcentration-time

profilesweresimilarbetweengabapentinsolutionandcapsuleformulations.Absolutebioavailabilityofa300mgoral

doseofGabapentinwasapproximately60%.Followingmultiple-doseadministrationatdosesof300mgand400mg,

Gabapentinbioavailabilitywasunchanged.

ThepresenceoffooddidnotaffectthebioavailabilityofGabapentin.

Gabapentinisnotmetabolisedinhumansanddoesnotinducehepaticmixedfunctionoxidaseenzymes.

GabapentineliminationfromplasmafollowingIVadministrationwasbestdescribedbylinearpharmacokinetics.

Eliminationhalf-life(T

)ofgabapentinrangedfrom5to7hours.Gabapentineliminationparameters,apparent

plasmaT

andrenalclearance(CL

)wereindependentofdoseandremainedunchangedfollowingrepeated

administration.Renalclearancewasthesoleeliminationpathwayforgabapentin.Sincegabapentinisnotmetabolised

inhumans,theamountofdrugrecoveredinurineisindicativeofgabapentinbioavailability.Followingasingle200mg

oraldoseof[C 14

]gabapentin,recoveryofradioactivitywasessentiallycompletewithapproximately80%and20%of

thedoserecoveredinurineandfaeces,respectively.

Asrenalfunction(whichwasdeterminedbycreatinineclearance)decreaseswithincreasingage,gabapentinoral

clearance,renalclearanceandelimination-rateconstantdecreaseproportionally.

Gabapentinpharmacokineticswasdeterminedin24healthypaediatricsubjectsbetweentheagesof4and12years.In

general,pharmacokineticparameterswerecomparabletothoseinadults.

5.3Preclinicalsafetydata

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

fortwoyears.Astatisticallysignificantincreaseintheincidenceofpancreaticacinarcelltumourswasfoundonlyin

maleratsatthehighestdose.

Peakplasmadrugconcentrationsandareasundertheconcentrationtimecurveinratsat2000mg/kgis10timeshigher

thanthetherapeuticconcentrationsinhumansgiventherecommendedmaximumtherapeuticdoseof3600mg/day.

Thepancreaticacinarcelltumoursinmaleratswerelowgrademalignancies,didnotaffectsurvival,didnot

metastasiseorinvadesurroundingtissue,andweresimilartothoseseeninconcurrentcontrols.Therelevanceofthese

pancreaticacinarcelltumoursinmaleratstocarcinogenicriskinhumansis,therefore,ofuncertainsignificance.

Gabapentinhasnogenotoxicpotential.ItwasnotmutagenicintheAmesbacterialplateincorporationassayoratthe

HGPRTlocusinmammaliancellsinthepresenceorabsenceofmetabolicactivation.Gabapentindidnotinduce

structuralchromosomeaberrationsinmammaliancellsinvitroorinvivo,anddidnotinducemicronucleusformationin

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LactoseMonohydrate

MaizeStarch

Talc

Capsuleshell:

Gelatin

Titaniumdioxide(E171)

Yellowironoxide(E172)

Redironoxide(E172)

PrintingInk:(OpacodeBlackS-I-8015HV)

Shellac(E904)

Vegetablecarbon

IndustrialMethylatedSpirit

AntifoamDC1510

PurifiedWater

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

18months.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Thecapsulesarepackedin10’sblistersconstitutedfrom250µmPVCand25µmaluminiumfoil.Packsizeof100

capsules.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

None.

7MARKETINGAUTHORISATIONHOLDER

MilpharmLimited

Ares,OdysseyBusinessPark

WestEndRoad

SouthRuislip,HA46QD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18November2003

Dateoflastrenewal:18November2008

10DATEOFREVISIONOFTHETEXT

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