GERICARB SR

Main information

  • Trade name:
  • GERICARB SR
  • Dosage:
  • 400mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GERICARB SR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/037/002
  • Authorization date:
  • 28-04-2000
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GericarbSR400mg,prolonged-releasetablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolongedreleasetabletcontains400mgcarbamazepine

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Prolongedreleasetablets

Whitetoyellowish,round,flat,cloverleafshapedtabletswithbevellededge,double-sidedcrossbreak-mark,4notches

ontheband.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

generalisedtonic-clonic

partialseizures

Fortheparoxysmalpainoftrigeminalneuralgia.

Fortheprophylaxisofmanicorhypomanicphasesofmanic-depressivepsychosisinpatientsunresponsiveorwith

contraindicationstolithiumtherapy.

4.2Posologyandmethodofadministration

Treatmentisstartedwithalowdosesetindividuallyaccordingtothetypeandseverityofsymptoms.Thedoseisthen

slowlyincreasedtotheoptimalmaintenancedosetosuitthepatient.

Dosesshouldbebasedonseizurecontrolandthedevelopmentofclinicalintolerance.Plasmalevelsareindicative

whetherapatientiswithinoroutsidethetherapeuticrangeinordertoexplainalackofseizurecontrolordevelopment

ofintolerance.Thismaybeparticularlyuseful,ifcombinationtherapyisused.

Therapeuticplasmalevelsofcarbamazepinearetypicallybetween4-12µg/lcorrespondingtoadosageof400-1200

mgperday.Amaximumdailydoseof1600-2000mgmayberequiredinadults.

Whenpatientsaretransferredfromanimmediate-releasecarbamazepineproduct,thesametotaldailydosewill

generallybesuitable.Inafewpatients,itmaybenecessarytoincreasethetotaldailydose,particularlywhenitisused

withotherantiepileptics.

Thetabletcanbedividedintoequalhalvesandthedailydoseisnormallytakenintwodivideddoses,duringoraftera

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Patientswhohavedifficultiesinswallowing,maytaketheprolongedreleasetabletsinwaterfollowingtheir

disintegrationintotheirgranules.Theprolongedreleasecharacteristicsofthetabletsaremaintainedforashortperiod

oftimeaftertheirsuspension.Thereforethesuspensionshouldbetakenimmediately.

Inpatientswithseverecardio-vasculardisease,liverdiseaseorrenaldamageandintheelderlyareduceddosemaybe

sufficient.

Furthermorethedoserequiredbysomepatientsmaydiffersubstantiallyfromtherecommendationforinitialand

maintenancedosebelow,duetoincreasedmetabolismcausedbyauto-inductionofhepaticenzymesordrug

interactionsduringcombinationtherapy.

Beforedecidingtoinitiatetreatment,patientsofHanChineseandThaioriginshouldwheneverpossiblebescreenedfor

HLA-B*1502asthisallelestronglypredictstheriskofseverecarbamazepine-associatedStevens-JohnsonSyndrome.

(seesection4.4)

Dosagerecommendations:

Epilepsy:

Treatmentisstartedwithalowdosesetindividuallyaccordingtothetypeandseverityofsymptoms.Thedoseisthen

slowlyincreasedtotheoptimalmaintenancedosetosuitthepatient.

Itisrecommendedthatacarbamazepinemonotherapytreatmentisusedwheneverpossible.Whentreatmentischanged

fromanotherdrugtocarbamazepinethedoseoftheotherantiepilepticdrugshouldbereducedslowly.

Ifachangeoftherapytoadifferentantiepilepticdrugisrequired,thechangemaynotbedoneinonesuddenstep,but

mustbedonegraduallyinsmallincrements.

Carbamazepinetherapyisdiscontinuedbyslowdosereduction.

Carbamazepineprolongedreleasetabletscanbebrokeninhalftotreatchildren/adultswithdivideddoseswhere

necessary.

*Carbamazepineprolongedreleasetabletsarenotgenerallysuitableforchildrenundertheageof5years.A

conventionaltabletorsyruppresentationofcarbamazepinemaybegiven.

Antiepileptictherapyisalong-termtreatment.

Ingeneral,adosereductionorwithdrawalofantiepilepticmedicationmaybeconsidered,whenpatientsareseizure-

freeforatleasttwoorthreeyears.Insteadofagedependantdoseadjustment,childrenmayoutgrowthedoseperkg

bodyweight.

Preventionofparoxysmalpainoftrigeminalneuralgia:

Theusualinitialdailydoseis100-400mg/daycarbamazepine.Thelowerinitialdosemaybesufficientforelderlyor

sensitivepatients.Thedoseisincreaseduntilthepatientisfreeofpain,generallywithadoseof600-800mg/day

Initialdose Maintenancedose

Adults 100–200mgonceortwicedaily 400–600mgmorningand

night

Children5-10years* 200mgatnight(or100mg

morningandnight) 100–200mgmorningand

200–400mgatnight

Children10-15years 200mgatnight(or100mg

morningandnight) 100–400mgmorningand

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thereafter,andmaypossiblybestoppedafterafewweeksoftreatment,ifthereisnorecurrenceofpain.

Prophylaxisofmanic-depressivepsychosis

Aninitialdoseof100-400mgdailyindivideddoses,increasedgraduallyuntilsymptomsarecontrolled,oratotalof

800mg,inexceptionalcasesmaximal1600mg,individeddosesisreached.Theusualmaintenancedoseis400-600

mgdaily,givenindivideddoses.

Prophylaxisofmanic-depressivepsychosisisalong-termtreatment.

Inordertopreventadruginteraction,itisnecessarytokeeptheplasmalevelofcarbamazepinebelow8µg/mland

lithiumatalowtherapeuticdosage(0.3-0.8mval/L),ifinexceptionalcasescarbamazepineisusedincombination

withlithiumfortheprophylaxisofmanicdepressivepsychosis,whichcannotbecontrolledwithlithiumtreatment

alone.Neuroleptictreatmentmustnotbedoneconcurrentlyandmusthavebeendiscontinuedatleast8weeks

beforehand.

TheimpairmentoftheabilitytoreactquicklyappearsinparticularwithcombinationtherapywithLithium.(seesection

4.7Effectsonabilitytodriveandusemachines)

4.3Contraindications

Carbamazepinemaynotbetakenwith:

knownbonemarrowdepression.

atrioventricularconductionabnormalities

hypersensitivityagainstcarbamazepine,orstructurallyrelateddrugs(forexampletricyclicantidepressants)or

againstoneoftheexcipients

acuteintermittentporphyria

Carbamazepinemustnotbeadministeredconcomitantlywithvoriconazole,asthereducedeffectivenessof

voriconazolebyinductionofhepaticenzymesinresponsetocarbamazepinemayleadtotreatmentfailureof

voriconazole.

4.4Specialwarningsandprecautionsforuse

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithanti-epilepticagentsinseveralindications.

Ameta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskofcarbamazepine.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

HLA-B*1502inindividualsofHanChineseandThaioriginhasbeenshowntobestronglyassociatedwiththeriskof

developingtheseverecutaneousreactionsknownasSteven-Johnsonsyndrome(SJS)whentreatedwithcarbamazepine.

Wheneverpossible,theseindividualsshouldbescreenedforthisallelebeforestartingtreatmentwithcarbamazepine.If

theseindividualstestpositive,carbamazepineshouldnotbestartedunlessthereisnoothertherapeuticoption.Tested

patientswhoarefoundtobenegativeforHLA-B*1502havealowriskofSJS,althoughthereactionsmaystillvery

rarelyoccur.

Itisnotdefinitelyknownwhetherallindividualsofsouteast-Asianancestryareatriskduetolackofdata.

ThealleleHLA-B*1502hasbeenshownnottoassociatedtoSJSintheCaucasianpopulation.

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conditions:

haematologicaldisturbances

disturbedsodiummetabolism

severecardiac,liverandkidneydysfunction

pregnancyandlactation

myotonicdystrophia,ascardiacconductionabnormalitiesarelikelyinthesepatients

Ifreactionssuchasfever,sorethroat,rash,ulcersinthemouth,easybruising,petechialorpurpurichaemorrhage,

nausea,yellowingoftheskin,andliverenlargementappears,thepatientshouldbeadvisedtoconsulthisphysician

immediately.

Inpatientswithseverecardio-vasculardisease,liverdiseaseorrenaldamageandintheelderlyaspecialobservationis

necessary.Dosesshouldbeadaptedtoeachcase.

Iftreatmentwithcarbamazepinehastobewithdrawn,alternativeanti-epilepticdrugsshouldbeprescribed.

Carbamazepinemaytriggerorexacerbateabsences.Itshouldthereforenotbeusedinpatientssufferingfromabsences.

Aswithotherantiepilepticdrugssomepatientsmayexperienceanincreaseinseizurefrequencyortheonsetofnew

typesofseizures.Thesephenomenamayalsobetheconsequenceofanoverdosage,adecreaseinplasma

concentrationsofconcomitantantiepileptictreatment,oraparadoxicaleffect.

Bloodcounts,plateletcountandserumbiochemistryincludingelectrolytesshouldbecheckedbeforecommencing

treatmentwithcarbamazepine.Bloodcountsshouldbeperformedonamonthlybasisforthefirstfivemonths.

Thereafter2-4timesayear.

Clinicalmonitoringisofprimaryimportanceduringtheentiretreatmentperiod.

Carbamazepinemustbediscontinued,ifsevereleucopeniaorthrombocytopeniaappear.

Liverfunctiontestsshouldalsobeperformedbeforecommencingtreatmentandperiodicallythereafter,particularlyin

patientswithahistoryofliverdiseaseandinelderlypatients.

Treatmentwithcarbamazepineshouldbesuspended,ifsignsandsymptomsofliverdysfunctiondevelop.

Treatmentshouldbediscontinuedimmediately,ifseverehypersensitivityreactionsoccur.

Amoderateloweringofthenumberofleukocytesorthrombocytesisoftenseenduringcarbamazepinetreatment,butis

usuallytransient.However,carbamazepinemustbediscontinuedifsevereleucopenia(mainlyneutropenia)or

thrombocytopeniaaccompaniedbyclinicalmanifestationsegfeverorsorethroatorsignificantdepressionofthebone

marrowappear.

ReportsofseveredermatologicalreactionsincludingLyell'ssyndrome(toxicepidermalnecrolysis),Stevens-Johnson

syndrome,andacutegeneralisedexanthematouspustulosisnecessitatesimmediatewithdrawal.Insuchcases,

carbamazepinerechallengeiscontraindicated.

Duetothepossibilityofphotosensitivity,patientsshouldavoidexcessiveexposuretosunlightduringcarbamazepine

therapy.

TheuseofCarbamazepineisnotrecommendedincombinationwithmonoamineoxidaseinhibitors(MAOIs);before

administeringCarbamazepine,MAOIsshouldbediscontinuedforaminimumof2weeks,orlongeriftheclinical

situationpermits.

Precautions:

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anticholinergicactivity.Theintra-ocularpressureofthesepatientsshouldbecheckedregularly.

Highdosesofcarbamazepinecouldresultinactivationoflatentpsychosisandpossiblyagitationorconfusionin

elderlypatients.

Carbamazepinemaydecreasetheeffectivenessoforalcontraceptives(seeSection4.5).

Alcoholingestionisnotrecommended,carbamazepinemayincreaseitseffects.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Anticonvulsants

Severalanticonvulsantdrugsareknowntobeinvolvedinaninteractionwithcarbamazepine;valproicacid,

ethosuximide,felbamate,lamotrigine,phenobarbital,primidoneandphenytoin.Bloodassaysoftheirrespective

plasmalevelsmayvaryfromonepatienttoanother,andmoreoverareusuallybi-directional.

Duetopotentialinteractionsduringcombinationtherapyofepilepsy,plasmalevelsshouldberegularlymonitored,and

dosageadjustedaccordinglyasrequired.

CytochromeP450inducers

Carbamazepineisastronginducerofseveraldrugmetabolisingliverenzymes.Concomitantuseofcarbamazepinemay

increasethemetabolismandthusdecreasetheplasmaconcentrationsofseveraldrugsthatareeliminatedby

metabolism.

ItshouldbenotedespeciallythatrifampicinisknowntoalsobeaverystronginducerofCYP450andreduces

carbamazepinelevels.

Monoamineoxidaseinhibitors

Becauseitisstructurallyrelatedtotricyclicanti-depressants,itisnotrecommendedtogivecarbamazepinein

combinationwithmonoamineoxidaseinhibitors(MAOIs).MAOIsshouldbediscontinuedatleast2weeksbefore

carbamazepinetherapyisstartediftheclinicalsituationpermits.

Drugsthatmaydecreasecarbamazepineplasmalevels:

Theplasmalevelofcarbamazepinemaybedecreasedbyotherenzymeinducerssuchas:phenobarbital,phenytoin,

primidone,felbamate(~25%),valproicacid,digoxin,theophylline,rifampicin,clonazepam,cisplatinordoxorubicin.

Ontheotherhandtheplasmaleveloftheactivecarbamazepine10,11epoxidemetabolitemaybeincreasedbyvalproic

acid,felbamate(~50%),primidone,clonazepamanddigoxin.

Duetopotentialinteractionsduringcombinationtherapyofepilepsy,plasmalevelsshouldberegularlymonitored,and

dosageadjustedaccordinglyasrequired.

SerumlevelsofcarbamazepinecanbereducedbyconcomitantuseoftheherbalpreparationSt.John’sWort

(Hypericumperforatum).Thisisduetoinductionofdrugmetabolisingenzymes,whichmaypersistforatleast2weeks

aftercessationoftreatmentwithSt.John’sWort.SerumlevelsofcarbamazepineshouldbemonitoredifSt.John’s

Wortisstartedorstoppedduringtreatment.

Drugsthatmayincreasecarbamazepineplasmalevels:

TheplasmaconcentrationsofcarbamazepinemaybeincreasedbyinhibitorsofCYP3A4:azoleantimycotics(e.g.

itraconazole,ketoconazole,fluconazole),macrolideantibiotics(e.g.erythromycin,josamycin,clarithromycinand

troleandromycin),isoniazid,calciumantagonists(e.g.verapamil,diltiazem),digoxin,acetazolamide,

dextropropoxyphene,propoxyphene,clonazepam,fluoxetine,viloxazine,danazol,nicotinamide(athighdosagein

adults),nefazodone,fluvoxamine,terfenadine,loratadine,grapefruitjuiceandproteaseinhibitorsforHIVtreatment

(e.g.ritonavir),possiblyalsocimetidine(doseshigherorequalto800mg),felbamateanddesipramine.Rarely

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RaisedplasmalevelsofcarbamazepinemayleadtothesymptomslistedunderUndesirableEffectsSection4.8e.g.

dizziness,tiredness,unsteadygait,doublevision.Thecarbamazepineplasmalevelshouldbecheckedandthedosage

reduced,ifnecessary,ifthesesymptomsappear.

Effectofcarbamazepineonplasmalevelsofotherdrugstakenconcomitantly:

Carbamazepinemaydecreasetheactivityofcertaindrugs.

Concurrentuseofcarbamazepinewiththefollowingdrugsubstancesmayrequiredoseadjustmenttoensurethe

requiredclinicalresponse,especiallywhenstartingordiscontinuingcarbamazepine–

clobazam,clonazepam,ethosuximide,primidone,tiagabine,valproicacid,lamotrigine,alprazolam,corticosteroids(e.g.

prednisolone,dexamethasone),digoxin,doxycycline,dihydropyridinese.g.felodipine,haloperidol,otherneuroleptic

drugssuchasrisperidone,clozapine,othertricyclicantidepressantslikeamitriptyline,nortriptyline,clomipramine,

imipramine;nefazodone;trazodone;topiramate,indinavir,ritonavir,methadone,tramadol,theophylline,anticoagulants

likewarfarin,phenprocoumon,dicoumarol,phenytoin(althoughphenytoinlevelsmaysometimesincrease),azole

antimycolyticssuchasvoriconazoleanditraconazole,bromperidol,olanzapine,quetiapine,praziquantel,caspofungin,

fentanyl,midazolam,phenazone,propranolol,methylphenidate,flunarizine,quinidineandhydroquinidine.

Inaddition,otherimmunosuppressantssuchastacrolimus,sirolimusandcyclosporin.

Productscontainingestrogensand/orprogestogens,includingoralcontraceptivesandhormonereplacementtherapy.

SeeSection4.4.SpecialWarningsandPrecautions.Reliablealternativecontraceptivemethodsshouldbeused).In

patientstakingthepillbreakthroughbleedingorspottingmayappearsuddenlyduetoadecreasedactivityofthe

contraceptive.

Carbamazepinemaylowertheplasmalevelofbupropionandmayincreasethelevelofitsmetabolite

hydroxybupropion.

Otherdrugcombinationstobetakenintoconsideration:

Concurrentuseofcarbamazepineandotherpsychotropicdrugs,e.g.neuroleptics,antidepressants,sedatives,hypnotics,

analgesics,sedativeantihistaminics,mayincreasetheoccurrenceofneurologicalsideeffects.

ThereisanindicationofahigherriskofdevelopingStevens-JohnsonSyndromewithconcomitantuseofneuroleptics.

Co-administrationofcarbamazepineandparacetamolmayreducethebioavailabilityofparacetamol(acetaminophen).

Riskofneurotoxiceffectsmaybeincreasedwithconcomitantuseofcarbamazepine(ataxia)andlithium(cerebellar

syndrome),despitethelithiumplasmaconcentrationsbeinginthenormalrange(seealso4.2PosologyandMethodof

Administration).Thefollowingadditionalneurotoxicsymptomscanbenoted:unsteadygait,horizontalnystagmus,

increasedinvoluntarymusclereflexes,muscletwitching.Theseneurologicaleffectsarereversibleafterstoppingthe

lithium.

Thehepatictoxicityofisoniazidmaybeincreasedbycarbamazepine.

Thecombinationofcarbamazepinewithhypokalaemicdiuretics(loopandthiazidediuretics)e.g.hydrochlorothiazide

andfurosemide,maycausehyponatraemia.

Concomitantadministrationofcarbamazepineandantiarrhythmics,cyclicantidepressantsorerythromycin,increases

theriskofcardiacconductionabnormalities.

Theactivityofmusclerelaxantslikepancuroniummaybereducedbycarbamazepine.Arapidrecoveryfrom

neuromuscularblockadeisthereforepossible.Patientsmustbesupervisedaccordinglyandthedosageoftherelaxant

increased,ifnecessary.

Carbamazepineplasmalevelsmustbecheckedduringconcurrenttreatmentwithisotretinoin(acnetreatment),asithas

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Carbamazepineappearstoincreasetheeliminationofthyroidhormonesandthusincreasethehormonerequirementof

hypothyroidpatients.Athyroidtestshouldthereforebeperformedatthestartanddiscontinuationofcarbamazepine

therapyinpatientsreceivingthyroidhormonesubstitution.Dosageadjustmentofthyroidhormonemayberequired.

Atoxicserotonin-syndromemaybeproduced,ifcarbamazepineistakentogetherwithdrugs,whichinhibitserotonin

re-uptake(e.g.fluoxetine).

Theseverehaematologicalsideeffectsofclozapinemaybeincreasedifusedincombinationwithcarbamazepine.

Anincreaseinhypersensitivity(e.g.rash,hypereosinophilia)mayoccurwhenprocarbazineistakenconcurrently.

AlcoholmayincreasetheCNSsideeffectsofcarbamazepine.Thereforepatientsshouldabstainfromalcoholduring

treatment.

4.6Pregnancyandlactation

Pregnancy:

Riskrelatedtoepilepsyandantiepilepticdrugsingeneral:

Ithasbeenshownthatintheoffspringofepilepticwomen,theprevalenceofmalformationsistwotothreetimes

greaterthantherateofabout3%foundinthegeneralpopulation.Inthetreatedpopulationanincreaseinmalformed

childrenhasbeennotedwithpolytherapy,howevertheextenttowhichthetreatmentand/ortheillnessarerespectively

responsiblehasnotbeenelucidatedasyet.

Themostfrequentlyencounteredmalformationsarelabialfusiondefectsandcardiovascularmalformations.

Risklinkedtocarbamazepine:

Animalexperimentshaveprovidedevidenceofateratogeniceffect.

Inhumans,thenumberofwomentreatedwithcarbamazepineinthefirsttermtrimesterofpregnancyinthevarious

prospectivestudiesisstilltoolimitedforafirmconclusiontobedrawnaboutwhetherthisriskofmalformationisreal.

However,somestudiessuggestthatcarbamazepinemaycauseanincreaseinneuraltubeclosureanomalies,e.g.spina

bifidaandmyelomeningocele(theriskreaches1%whichis10-foldhigherthanthenormalrate),malformationsfor

whichanantenataldiagnosticispossible.

Takingthesedataintoconsideration:

Carbamazepinemaybeusedduringpregnancyonlyaftercarefulrisk/benefitevaluation.Womenofchildbearingage

shouldbeadvisedofthenecessitytoplanandensuresupervisionofpregnancy.

Ifawomanispregnantorplanstobecomepregnant,thenecessityoftreatmentshouldbereconsidered.Inepilepsy,if

possible,carbamazepineshouldbeprescribedasamonotherapy,andminimumeffectivedosesshouldbegiven,based

onclinicalresponseonly.Monitoringofplasmaconcentrationsofunboundcarbamazepinemaybeuseful(seealso4.2

PosologyandMethodofAdministration).

Duringthepregnancy,aneffectiveanti-epilepticcarbamazepinetreatmentmustnotbeinterrupted,sincethe

aggravationoftheillnessisdetrimentaltoboththemotherandthefoetus.

Monitoringandprevention:Thepreventionofneuraltubeanomaliesbyfolicacidinpregnantwomentreatedwith

carbamazepineisnotfullydemonstratedatpresent.However,takingintoaccountthatfolicaciddeficiencyduetothe

enzymeinductioncausedbycarbamazepinemaybeacontributoryfactorforfoetalabnormality,itmaythereforebe

beneficialtotakefolicacidbefore(2months)andduringpregnancy.

Patientsshouldbeinformedoftheincreasedriskofmalformations.Aspecificantenataldiagnosiscanbeproposed

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Inthenew-bornchild:

Enzymaticinducershaveprovoked:

Uncommon:bleedingdisordersoccurringinthefirst24hoursofthelifeofatreatedmother’schild.Preventionbyoral

vitaminK1tothemother,inthemonthpriortothebirth,andanadapteddosetothenew-bornchildatthemomentof

birth,seemappropriate.

Rarely:problemswiththephosphocalcicmetabolismandbonemineralisation.

Lactation:

Carbamazepineanditsmainmetabolite,carbamazepine-epoxide,arebothpresentinbreastmilkinconcentrationsof

about25–60%ofthetotalplasmaconcentration.Duetothepossibleonsetofnon-dose-dependentadverseeffectsin

theneonate,breast-feedingisnotrecommendedduringtreatmentforsafetyreasons.Breastfeedingshouldbestoppedif

signsofsedationbecomeapparent.

4.7Effectsonabilitytodriveandusemachines

Theproducthasamajorinfluenceonthepatients'reactions,especiallyintheearlystagesoftreatment.Thismaybe

furtherinfluencedbyhigherdoselevelsortheuseofcarbamazepineincombinationwithothercentrallyactingdrugs

orinconjunctionwithalcoholconsumption.Patientsshouldbewarnedofthepossiblehazardswhendrivingor

operatingmachinery.

4.8Undesirableeffects

Thefollowingundesirableeffectsappeardependentonthedoseinparticularatthestartoftherapy,toohighinitialdose

orinelderlypatients.Thesesymptomsmayabatespontaneouslywithinafewdaysorifthedoseistransientlyreduced:

Dizziness,headache,ataxia,drowsiness,fatigue,diplopia,nausea,vomiting.

Sideeffectslistedaccordingtoorgansystemwiththefrequencyestimateverycommon( ≥1/10),common(≥1/100,

≤:1/10),uncommon(≥1/1,000,≤1/100),rare(≥1/10,000,≤1/1,000)andveryrare(≤1/10,000includingisolated

reports):

Bloodandthelymphaticsystemdisorders

Uncommontocommon:Changesinbloodcounti.e.leucocytosis,eosinophilia,leucopeniaandthrombocytopenia.

Accordingtoliteraturesourcesthemostfrequentdisorderisbenignleucopenia,10%ofthecasesbeingofatransient

nature,2%persistent.

Isolatedcasesofevenlifethreateningdamageofbloodcellswerereportedi.e.agranulocytosis,aplasticanaemiaand

otherformsofanaemia(haemolytic,megaloblastic),pureredcellaplasia,acuteintermittentporphyria,reticulocytosis,

folicaciddeficiencyandlymphadenopathy,spleenenlargement.

Immunesystemdisorders

Rare:Delayedmulti-organhypersensitivitydisorderwithfever,skinrashes,vasculitis,swollenlymphnodes,painful

joints(arthralgia),leucopenia,eosinophilia,hypogammaglobulinaemia,enlargementofliverandspleenoralteredliver

functiontestoccuringinvariouscombinations.Otherorganssuchaslung,kidney,pancreas,colonandcardiacmuscle

mayalsobeaffected.

Isolatedcasesofageneralisedacuteallergicreactionandasepticmeningitiswithmyoclonusandeosinophiliahave

beenobserved.

PsychiatricDisorders

Uncommon:confusionandagitationinelderlypatient;depressivedisorders,aggressivebehaviour,thinkingdifficulties,

hallucinations.

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Veryrarelyphobiasandmooddisturbances,includingmania.

NervousSystemDisorders

Common:dizziness,somnolence,sedation,drowsiness,ataxia,(atacticandcerebraldisturbances).

Uncommon:headache,lackofdrive,

Rare:Involuntarymovementslikeasterixis,ticsornystagmus.Inelderlyorpatientswithcerebraldamagedyskinetic

disturbanceslikeorofacialdyskinesia(involuntarymovementsofthefacelikemakingfaces)andchoreoathetotic

disorders(screwedupmovements)mayappear.

Veryrare:Speechdisorders,paraesthesia,muscleweakness,peripheralneuritis,paresisofthelegsandtaste

disturbance

Mostoftheseeffectsdisappearduringthefirst8-14daysoftreatmenteitherspontaneouslyorafteratransientdosage

reduction.Forthisreasontreatmentshouldbestartedwithalowdose,whichisgraduallyincreased.

Casesofneurolepticmalignantsyndromehavebeenreported.Thecontributionofcarbamazepinetodevelopmentof

thissyndrome,especiallyinconjunctionwithneuroleptics,isunclear

Eyedisorders

Rare:transientvisualdisturbances,likeaccommodationdisorders,diplopia,nystagmus,lensopacities.

Veryrare:Conjunctivitisandretinotoxicity.

Earandlabyrinthdisorders

Uncommon:tinnitus.

Veryrare:changeinpitchperception,tinnitus,hypoacusisandhyperacusis.

Cardiacdisorders

Rare:AV-block,inisolatedcaseswithsyncopeandhypertensionorhypotension.

Highdoseofcarbamazepineinparticularmayleadtoafallinbloodpressure.

Veryrare:Bradycardia,cardiacarrhythmias.

Isolatedcases:worseningofcoronaryarterydiseaseinparticularinelderlyorpatientswithknowndisturbancesof

cardiacfunction.

Vasculardisorders

Thrombophlebitisandthrombo-embolismhavebeenreported.

Respiratory,thoracicandmediastinaldisorders

Isolatedcasesofpulmonaryhypersensitivityreactionswithfever,dyspnoea,pneumonitisorpneumonia(alveolitis),

lungfibrosis.

Gastro-intestinaldisorders

Uncommon:Lossofappetite,drymouth,nausea,vomiting.

Rare:Diarrhoea,constipation.

Veryrare:Abdominalpain,stomatitis,gingivitis,glossitis;Theseeffectsusuallydisappearduringthefirst8-14days

oftreatmenteitherspontaneouslyorafteratransientdosagereduction.(lowinitialdose).

Carbamazepinemayinducepancreatitisinveryrarecases.

Hepato-biliarydisorders

Common:elevatedgamma-GT(duetohepaticenzymeinduction),usuallynotclinicallyrelevant.

Uncommon:elevatedalkalinephosphatase,rarelytransaminases.

Rarely:Jaundice.

Isolatedcasesofhepatitis(cholestatic,hepatocellular,granulomatous,mixedtype)andveryrarelyliverfailure.

Skinandsubcutaneoustissuedisorders

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Raretouncommonly:alopecia,diaphoresisandvasculitisappeared.

Veryrare:alterationsinskinpigmentation,acne,sweating,hirsutismexfoliativedermatitis,erythroderma,Lyell-

syndrome,photosensitivity,erythemaexudativum,multiformeandnodosum,Stevens-Johnsonsyndrome,purpura,

lupuserythematosusdisseminatuswerereported.acutegeneralisedexanthematouspustulosis

Musculoskeletal,connectivetissueandbonedisorders.

Veryrare:Arthralgia,musclepainorcramp.

Renalandurinarydisorders

Rare:Renalimpairmentsuchasproteinuria,haematuria,oliguria,additionallyothermicturitiondisorderslikedysuria,

urinaryfrequencyandurinaryretention.

Veryrare:isolatedcasesofrenalfailure,whicharepossiblyduetotheantidiureticeffectofcarbamazepine,interstitial

nephritisandelevatedBUN/azotaemina.

Reproductivesystemandbreastdisorders

Rarely:gynaecomastia;galactorrhoea.

Isolatedcasesofsexualdysfunctionlikeimpotence,decreasedlibidoandimpairedmalefertility.

Congenitalandfamilial/geneticdisorders

Twocasesofacuteintermittentporphyriawerereported.

Generaldisordersandadministrationsiteconditions

Common:fatigue.

Investigations

Uncommon:reducedplasmaosmolalityduetoanantidiuretichormone(ADH)–likeeffect,leadinginrarecasesto

waterintoxicationaccompaniedbylethargy,vomiting,headache,mentalconfusion,neurologicalabnormalities.

Veryrarely:elevatedlevelsofcholesterol,includingHDLcholesterol,andtriglycerides.

Carbamazepinemayincreasethemetabolismof25-OH-Cholecalciferolleadingtoadecreasedcalciumlevel,which

rarelycausesosteomalacia.

CarbamazepinemaylowertheplasmalevelsoffolicacidandvitaminB12,andmayincreasetheplasmalevelof

homocysteine.

Abnormalthyroidfunctiontests:decreasedL-thyroxine(FT

,T

,T

)andincreasedTSH,usuallywithoutclinical

manifestations.

4.9Overdose

Carbamazepineoverdosehasbeenreportedonlywithveryhighdoses(4-20g).Plasmalevelswerealwaysabove

20µg/ml.Aplasmalevelof38µg/mlwasnotlethalforthepatient.Lethalcasesofcarbamazepineoverdosehavebeen

reportedinliterature.

Symptoms:

Thepresentingsignsandsymptomsofoverdosageinvolvethecentralnervous,cardiovascularorrespiratorysystems.

Centralnervoussystem:CNSdepression,disorientation,somnolence,agitation,hallucination,coma;blurredvision,

slurredspeech,dysarthria,nystagmus,ataxia,dyskinesia,initiallyhyperreflexia,laterhyporeflexia;convulsions,

psychomotordisturbances,myoclonus,hypothermia.

Respiratorysystem:Respiratorydepression,pulmonaryoedema.

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arrhythmias,conductiondisturbancewithwideningofQRScomplex;syncope.

Gastro-intestinalsystem:Vomiting,delayedgastricemptying,reducedbowelmotility.

Renalfunction:Retentionofurine,oliguriaoranuria;fluidretention,waterintoxicationduetoADH-likeeffectof

carbamazepine.

Laboratoryfindings:Hyponatraemia,possiblymetabolicacidosis,possiblyhyperglycaemia,increasedmuscle

creatininephosphokinase.

Managementofsymptoms

Thereisnospecificantidoteforcarbamazepineoverdose.

Managementofsymptomsduetooverdosagewillvaryaccordingtothepatient'scondition.Thisincludesadmissionto

hospital.Measurementoftheplasmalevelstoconfirmcarbamazepinepoisoningandtoascertainthesizeofthe

overdose.Evacuationofthestomach,gastriclavage,andadministrationofactivatedcharcoal.Supportivemedicalcare

inanintensivecareunitwithcardiacmonitoringandcarefulcorrectionofelectrolyteimbalance,ifrequired.

Specialrecommendations:Hypotension:administerdopamineordobutamineiv.Disturbancesofcardiacrhythm:tobe

managedonanindividualbasis.

Convulsions:administerabenzodiazepine(egdiazepam)oranotheranticonvulsant,egphenobarbitone(withcaution

becauseofincreasedrespiratorydepression)orparaldehyde.

Hyponatraemia(waterintoxication):fluidrestrictionandslowcarefulNaCl0.9%infusioniv.Thesemeasuresmaybe

usefulinpreventingbraindamage.

Charcoalhaemoperfusionhasbeenrecommended.Forceddiuresis,haemodialysis,andperitonealdialysishavebeen

reportednottobeeffective.

Relapseandaggravationofsymptomatologyonthe2 nd

and3 rd

dayafteroverdose,duetodelayedabsorption,should

beanticipated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCode:N03AF01-Carbamazepineisadibenzazepinederivativewithantiepileptic,neurotropicandpsychotropic

properties.

Itisthoughttoblockcyclic-AMPmediatedcalciuminfluxassociatedwithtransmitterrelease,anditisknowntobean

adenosinereceptorantagonist:eitheroftheseactionsmightaccountforitsanti-epilepticaction.Workinanimalshas

shownthatithasinhibitoryeffectsonhippocampaldischargesanditalsoinhibitsthereticulo-thalamicand

thalamocorticalprojectionswhichareinvolvedintonic-clonicseizures.

Antiepilepticshavemembrane-stabilisingpropertieswhichhavebeenfoundusefulinthereliefofneurogenicpain

especiallywherethereisalancinatingelement,asintrigeminalneuralgia.

5.2Pharmacokineticproperties

Absorption

Carbamazepineisalmostcompletelyabsorbedbuttherateofabsorptionisslowandmayvarybetweenpatients.

Peakplasmaconcentrationsoftheunchangedactivesubstanceareattainedwithin24hours.Thebioavailabilityof

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toplasma.

Evaluationofliteratureallowstheconclusionconcerningtherapeuticandtoxicplasmalevelsthatseizuresare

controlledatplasmalevelsbetween4and12µg/ml,levelsabove20µg/mlresultedinadeteriorationofsymptoms.

Controlofpainoftrigeminalneuralgiawaseffectiveatplasmalevelsbetween5and18µg/ml.Sideeffectsstart

appearingatplasmalevelsabove8-9µg/ml.

Distribution

TheconcentrationofunchangedsubstanceintheCSFandsalivarepresentstheunboundportioninplasma,ie,20-30%

oftotalplasmaconcentration.Inbreastmilktheconcentrationis25-60%oftotalplasmaconcentration.Carbamazepine

crossestheplacentalbarrier.Apparentvolumeofdistribution:0.8-1.5L/kg.

Metabolism

Carbamazepineisextensivelymetabolisedintheliver,mainlybyoxidativepathwaysofwhichonlythemetabolite

carbamazepine-epoxideispharmacologicallyactive.Thismayconstituteupto30%ofthecirculatingactivematerial

originalityascarbamazepine.Theinactive10,11-diolrepresentsthefinalstageofcarbamazepinebiotransformation.In

children,therelativelyhighrateofmetabolismofthedrugmayrequirehigherdose(inmg/kgb.w.)ofcarbamazepine

tomaintaintherapeuticconcentrations.

Elimination

Onlyabout1%oftheadministereddoseisexcretedintheurineintheunchangedform.Agreaterpartisexcretedin

theurinealmostentirelyintheformofitsmetabolites;someisexcretedinfaeces.

Theeliminationhalf-lifeofunchangeddrugintheplasmaaveragesapproximately36hoursfollowingasingledose,

whereasafterrepeatedadministration,itaveragesonly16-24hours,dependingonthedurationofthemedication.In

patientsreceivingco-medicationwithotherenzyme-inducingdrugssuchasphenytoin,phenobarbitone,half-lifevalues

averaging9-10hourshavebeenobserved.

Specialpopulation

Carbamazepineshouldbeusedwithcautioninpatientswithrenalimpairment.

Inadvancedhepaticdisease,carbamazepinemetabolismmaybeimpaired.

Thepharmacokineticsofcarbamazepineareunalteredintheelderlybutitsmetabolismmaybeaffectedbyhepatic

dysfunction.Thecontrolledreleaseformulationofcarbamazepineproducesasubstantialreductioninintra-dose

fluctuationsincarbamazepineconcentrationsandtolerabilityandseizurecontrolinpatientswithepilepsymaybe

improved.

Thecontrolledreleaseformulationshouldbeconsideredinpatientsreceivinghighdoseswhosufferintermittent

adverseeffectssuchasdiplopia,nausea,dizzinessandtirednessandmayoffertheopportunitytoreducethedosage

regimen.

5.3Preclinicalsafetydata

Invitroandinvivomutagenicitytestswithcarbamazepinedidnotgiveanindicationofamutagenicpotential.A

carcinogenicitystudyovertwoyearsinratsindicatedanincreasedincidenceofhepatomasinrats.However,thereisno

evidencethatthisobservationisofimportanceforthetherapeuticuseofcarbamazepineinhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

AmmoniomethacrylatecopolymertypeB

Methacrylicacid-ethylacrylatecopolymer(1:1)

Triacetin

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Microcrystallinecellulose

Crospovidone

Colloidalanhydroussilica

Magnesiumstearate

Sorbicacid

Sodiumhydroxide

Sodiumlaurilsulphate

Polysorbate80

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage.

6.5Natureandcontentsofcontainer

Child-proofcontainers:

PVC/PVDCBlisterwithaluminium/pergamynliddingorPVC/PVDC

Blisterwithcross-perforatedsoftaluminiumlidding

Packscontaining:

20,28,30,50,56,60,84,90,100,112,120,150,168,180,200,250or500prolongedreleasefilmcoatedtablets

Samplepackwith30prolongedreleasefilmcoatedtablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd(T/AGerardLaboratories),

35-36BaldoyleIndustrialEstate,

GrangeRoad,

Dublin13.

8MARKETINGAUTHORISATIONNUMBER

PA0577/037/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

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Dateoflastrenewal:07January2004

10DATEOFREVISIONOFTHETEXT

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