GABITRIL

Main information

  • Trade name:
  • GABITRIL Film Coated Tablet 2.5 Milligram
  • Dosage:
  • 2.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GABITRIL Film Coated Tablet 2.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0827/003/001
  • Authorization date:
  • 22-03-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0827/003/001

CaseNo:2082959

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

CephalonUKLimited

1AlbanyPlace,HydeWay,WelwynGardenCity,Hertfordshire,AL73BT,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gabitril2.5mg,film-coatedtablet

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom19/05/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gabitril2.5mg,film-coatedtablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachGabitril2.5mgtabletcontains:

Tiagabine2.5mg(ashydrochloridemonohydrate)

Excipients:

EachGabitril2.5mgfilm-coatedtabletcontains29mgoflactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Gabitril2.5mgfilm-coatedtabletisawhite,roundbiconvexfilm-coatedtabletembossedononesidewith"254".

4CLINICALPARTICULARS

4.1TherapeuticIndications

Add-ontreatmentofpartialseizureswithorwithoutsecondarygeneralisationwhicharenotsatisfactorilycontrolled

withotheranti-epilepticdrugs.

Thedrugshouldonlybeusedinadultsandadolescentsover12years.

4.2Posologyandmethodofadministration

Gabitrilisgivenorallyandshouldbetakenwithmeals.

Dosingschemesmayneedtobeindividualisedbaseduponapatient’sparticularcharacteristicssuchasage,liver

functionandconcomitantmedications(seesection4.5).

Theinitialdailydoseshouldbetakenasasingledoseordividedintotwodoses.Thedailymaintenancedoseshouldbe

dividedintotwoorthreesingledoses.

Tiagabineisnotrecommendedforuseinchildrenbelow12yearsduetoalackofdataonsafetyandefficacy.(See

section4.4).

Adultsandadolescentsover12years:

Inassociationwithenzyme-inducingdrugs:

Theinitialdailydoseis5-10mgtiagabine,followedbyweeklyincrementsof5-10mg/day.Theusualmaintenance

doseinpatientstakingenzyme-inducingdrugsis30-50mg/day.Dosesupto70mg/dayarewelltolerated.

Inassociationwithnonenzyme-inducingdrugs:

Theinitialdailydoseis5-10mgtiagabine,followedbyweeklyincrementsof5-10mg/day.

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Elderly:Thepharmacokineticpropertiesoftiagabinedonotseemtobesignificantlymodifiedintheelderly.However,

onlylimitedinformationisavailableontheuseofGabitrilinelderlypatients.Itisthereforerecommendedtouse

tiagabinewithcautioninthisagegroup.

Patientswithrenalinsufficiency:Renalinsufficiencydoesnotaffectthepharmacokineticsoftiagabine,thereforethe

dosagedoesnotneedtobemodifiedinthistypeofpatient.

Patientswithimpairedliverfunction:Tiagabineismetabolisedintheliverandsincethepharmacokineticsoftiagabine

inpatientswithmildtomoderateimpairedliverfunctionismodified(seeSection5.2),theGabitrildosageshouldbe

adjustedbyreducingtheindividualdosesand/orprolongingthedoseintervals.

4.3Contraindications

Gabitrilshouldnotbeusedincaseof:

Hypersensitivitytotiagabineortoanyoftheexcipients.

Severelyimpairedliverfunction.

4.4Specialwarningsandprecautionsforuse

Intheabsenceofclinicaldata,Gabitrilisgenerallynottoberecommendedingeneralisedepilepsy,particularlythe

idiopathicformswithabsencesandLennoxGastautsyndrome,orsimilarforms.Furthermore,inviewofthe

GABAergicmodeofactionoftiagabineandthedatafromanimalstudies,ariskofaggravationofabsencesinpatients

withgeneralisedepilepsytreatedwithGabitrilcannotbeexcluded.

Tiagabineisnotrecommendedforuseinchildrenbelow12yearsduetoalackofdataonsafetyandefficacy.(See

section4.2).

Post-marketingreportshaveshownthatGabitrilusehasbeenassociatedwithnewonsetseizuresandstatusepilepticus

inpatientswithoutepilepsy.Althoughseizureshavebeenreportedinpatientstakingnormaldailydosesoftiagabine,

mostofthecaseshavebeenreportedincontextofoverdoses(seesection4.9)orafteratoofasttitrationrate.Other

confoundingfactorsthatmayhavecontributedtodevelopmentofseizuresinnonepilepticpatientsincludeunderlying

medicalconditionsorconcomitantmedicationsthatcanreduceseizurethreshold.

SafetyandeffectivenessofGabitrilhavenotbeenestablishedforanyindicationotherthanadd-ontreatmentofpartial

seizureswithorwithoutsecondarygeneralizationinadultsandadolescentsover12yearsnotsatisfactorycontrolled

withotheranti-epilepticdrugs.

Aswithallotheranti-epilepticdrugs,abruptdiscontinuationofthetreatmentmaycauserecurrenceofseizures.Itis

thereforerecommendedtoreducethedosegraduallyoveraperiodof2-3weeks.

Inpatientswithahistoryofseriousbehaviouralproblemsincludinggeneralisedanxietyanddepression,thereisarisk

ofrecurrenceofthesesymptomsduringtreatmentwithGabitril,ascanbeseenwithcertainotheranti-epilepticdrugs.

Treatmentshouldthereforebestartedwithalowinitialdoseundercarefulclinicalobservation.

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithantiepilepticagentsinseveralindications.

Ameta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskfortiagabine.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

Aswithotheranti-epilepticdrugs,somepatientsmayexperienceanincreaseinseizurefrequencyortheonsetofnew

typesofseizureswithtiagabine.Thesephenomenamaybetheconsequenceofanoverdose,adecreaseinplasma

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Spontaneousecchymoseshavebeenreported.Therefore,ifecchymosesareobserved,fullbloodcountincluding

plateletcountshouldbeperformed.

Rarecasesofvisualfielddefectshavebeenreportedwithtiagabine.Ifvisualsymptomsdevelop,thepatientshouldbe

referredtoanophthalmologistforfurtherevaluationincludingperimetry.

Duetothepresenceoflactose,patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantusewithdrugsinvolvingCYP3A4/5metabolism:

Anti-epilepticagentswhichinducehepaticenzymes(CYP450)suchasphenytoin,carbamazepine,phenobarbital,and

primidoneenhancethemetabolismoftiagabine.

Rifampicine(CYPinducer)enhancesthemetabolismoftiagabine.

Incaseofcombinationwithoneorseveralofthesedrugs(anti-epilepticagents,rifampicine),thedoseoftiagabine

couldbeadapted:increaseofdailydoseand/ormorefrequentadministrationinordertoachievetheclinicalresponse.

Concomitantusewithnon-inducingdrugs:

Followingagivendoseoftiagabine,theestimatedplasmaconcentrationinnon-inducedpatientsismorethantwicethat

inpatientsreceivingenzyme-inducingagents.Toachievesimilarsystemicexposuresoftiagabine,non-induced

patientsrequirelowerandlessfrequentdosesoftiagabinethaninducedpatients.Thesepatientsmayalsorequirea

slowertitrationoftiagabinecomparedtothatofinducedpatients.

Gabitrildoesnothaveanyclinicallysignificanteffectontheplasmaconcentrationsofphenytoin,carbamazepine,

phenobarbital,valproate,warfarin,digoxin,theophyllineandhormonesfromoralcontraceptives.

Cimetidinedoesnothaveaclinicallysignificanteffectontiagabineplasmalevels.

4.6Pregnancyandlactation

Animalexperimentshavenotshownateratogeniceffectoftiagabine.

Studiesinanimalshave,however,revealedperi-andpost-nataltoxicityoftiagabineinveryhighdoses.

ClinicalexperienceoftheuseofGabitrilinpregnantwomenislimited.

NoinformationonGabitrilduringbreast-feedingisavailable.

Consequently,asaprecautionarymeasure,itispreferablenottouseGabitrilduringpregnancyorbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

GabitrilmightcausedizzinessorotherCNSrelatedsymptoms,especiallyduringinitialtreatment.Therefore,caution

shouldbeshownbypatientsdrivingvehiclesoroperatingmachinery.

4.8Undesirableeffects

Adverseeventsaregenerallymildtomoderate.Mosteventsoccurduringthetitrationphaseandareoftentransient.

Thefrequencyofadversereactionslistedbelowisdefinedusingthefollowingconvention:verycommon( ≥1/10);

common( ≥1/100,<1/10);uncommon(≥1/1,000,<1/100);rare(≥1/10000<1/1,000),unknown(cannotbe

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Psychiatricdisorders

Verycommon:Depressedmood,Nervousness,Mentalconcentrationdifficulty

Common:Emotionallability.

Rare:Confusion,Paranoïdreactions(hallucination,agitationanddelusion).

Nervoussystemdisorders

Verycommon:Dizziness,Tremor,Somnolence

Rare:Non-convulsivestatusepilepticus,

Unknown:Encephalopathy

Eyedisorders

Rare:Visualfielddefects(seesection4.4)

Gastro-intestinalsystemdisorders

Common:Diarrhoea

Skinandsubcutaneoustissuedisorders

Common:Ecchymoses

Generaldisordersandadministrationsiteconditions

Verycommon:Tiredness

Investigations

Rare:Slow-downEEGassociatedwitharapidtitrationphaseortiagabineincreasingdose

Postmarketing:

Post-marketingreportshaveshownthatGabitrilusehasbeenassociatedwithnewonsetseizuresandstatusepilepticus

inpatientswithoutepilepsytreatedbytiagabineforunapprovedindication(seesection4.4).

4.9Overdose

SymptomsmostoftenaccompanyingGabitriloverdose,aloneorincombinationwithotherdrugs,haveincluded

seizures,includingstatusepilepticus,inpatientswithandwithoutunderlyingseizuredisorders,muteandwithdrawn

appearanceofthepatient,coma,ataxiaorincoordination,somnolence,dizziness,confusion,impairedspeech,agitation,

myoclonus,spikewavestupor,tremors,vomitingandhostility.Respiratorydepressionhasbeenseeninthecontextof

seizures.

Frompost-marketingexperience,therehavebeennoreportsoffataloverdosesinvolvingGabitrilalone(dosesupto

720mg),althoughanumberofpatientsrequiredintubationandventilatorysupportaspartofthemanagementoftheir

statusepilepticus.

Incaseofoverdose,standardsymptomatictreatmentisrecommended.Hospitalisationcanberecommendedincaseof

severeoverdoses.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-epileptic/fattyacidderivative

ATCcode:N03AG06

TiagabineisapotentandselectiveinhibitorofbothneuronalandglialGABAuptake.

TreatmentwithGabitrilleadstoanincreaseinbrainlevelsofGABA,themajorinhibitoryneurotransmitterinthe

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Tiagabinelackssignificantaffinityforotherneurotransmitterreceptorbindingand/oruptakesites.

5.2Pharmacokineticproperties

Absorption

Tiagabineisrapidlyandvirtuallycompletelyabsorbedfromthegastro-intestinaltract,withanabsolutebioavailability

of89%.AdministrationofGabitrilwithfoodresultsinalowerplasmaconcentrationpeakandadelayofthepeak,but

withoutchangingthetotalquantityabsorbed.

Distribution

Thevolumeofdistributionisapproximately1l/kg.Plasmaproteinbindingoftiagabineisabout96%.

Biotransformation/Elimination

Tiagabineiswidelymetabolisedinhumans,mainlybytheliverCYP3Asystem.

ThereisnoevidencethattiagabinecausesinductionorinhibitionofcytochromeP450.Conversely,otherantiepileptics

suchasphenytoin,carbamazepine,phenobarbital,andprimidoneincreasethehepaticclearanceoftiagabinewhen

givenconcomitantly.

Theplasmahalf-lifeoftiagabinewhichisnormally7-9hours,isreducedto2-3hoursincombinationwiththese

substances.

Intheurinelessthan1%isexcretedunchangedand14%astwo5-oxo-thioleneisomers.Therestisexcretedinfaeces

asmetabolites.Noactivemetaboliteshavebeenidentified.

Hepaticinsufficiency

Astudyinpatientswithmildtomoderateimpairedliverfunctionhasshowna50%increaseoftheplasma

concentrationpeakoftiagabineanda70%increaseoftheareaunderthecurve.Thehalf-lifeoftiagabineisprolonged

withthedegreeofimpairmentofliverfunction.However,nopatientswithsevereimpairmentofliverfunctionwere

includedinthestudy(seesection4.3).

Thedosageoftiagabineshouldbemodifiedinpatientswithmildtomoderateimpairedliverfunction(seesection4.2).

5.3Preclinicalsafetydata

Alongtermcarcinogenicitystudyinratsrevealedaslightlyincreasedincidenceofhepatocellularadenomasinfemales

inthehighdose(200mg/kg).Thedrugisnon-genotoxic.Theclinicalrelevanceoftheseabnormalitiesisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Cellulose,microcrystalline(E460)

Ascorbicacid(E300)

Lactoseanhydrous

Starch,pregelatinised(maize)

Crospovidone

Silica,colloidalanhydrous(E551)

Hydrogenatedvegetableoil(Type1)

Stearicacid

Magnesiumstearate

Film-coating:

Hypromellose

Hydroxypropylcellulose(E463)

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotrefrigerateorfreeze.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Childresistant,whitepolyethylenebottleswithwhitepolypropylenescrewclosures.Eachbottlecontainsahighdensity

polyethylenecanisterofactivatedclaydesiccant.

Packscontaining20,30,50,100(2bottlesof50)and200(4bottlesof50)tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

CephalonUKLtd.

1AlbanyPlace

HydeWay

WelwynGardenCity

HertfordshireAL73BT

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0827/003/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 22March2002

Dateoflastrenewal: 14June2006

10DATEOFREVISIONOFTHETEXT

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