EPILIM ENTERIC

Main information

  • Trade name:
  • EPILIM ENTERIC
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Tablets Gastro-Resistant
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPILIM ENTERIC
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1151/117/001
  • Authorization date:
  • 31-07-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EpilimEnteric200mgGastro-resistantCoatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachgastro-resistanttabletcontains200mgofsodiumvalproate

Excipients:Containsamaranthlake(E123)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Gastro-resistantcoatedtablets.

ProductimportedfromtheUK:

Lilac,biconvex,gastro-resistantcoatedtablet,plainonbothsides

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inthetreatmentofgeneralised,partialorotherepilepsy.

4.2Posologyandmethodofadministration

EpilimEnteric200mggastro-resistantcoatedtabletsarefororaladministration.

Dailydosagerequirementsvaryaccordingtoageandbodyweight.

Epilimtabletsmaybegiventwicedaily.Tabletsshouldbeswallowedwholeandnotcrushedorchewed.

InpatientswhereadequatecontrolhasbeenachievedEpilimChronoformulationsareinterchangeablewithother

Epilimconventionalorprolongedreleaseformulationsonanequivalentdailydosagebasis.

Dosage

Usualrequirementsareasfollows:

Adults

Dosageshouldstartat600mgdailyincreasingby200mgatthree-dayintervalsuntilcontrolisachieved.Thisis

generallywithinthedosagerange1000mgto2000mgperday,i.e.20-30mg/kg/daybodyweight.Whereadequate

controlisnotachievedwithinthisrangethedosemaybefurtherincreasedto2500mgperday.

Childrenover20kg

Initialdosageshouldbe400mg/day(irrespectiveofweight)withspacedincreasesuntilcontrolisachieved;thisis

usuallywithintherange20-30mg/kgbodyweightperday.Whereadequatecontrolisnotachievedwithinthisbody

rangethedosemaybeincreasedto35mg/kgbodyweightperday.

Childrenunder20kg

20mg/kgofbodyweightperday;inseverecasesthismaybeincreasedbutonlyinpatientsinwhomplasmavalproic

acidlevelscanbemonitored.Above40mg/kg/day,clinicalchemistryandhaematologicalparametersshouldbe

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UseintheElderly

AlthoughthepharmacokineticsofEpilimaremodifiedintheelderly,theyhavelimitedclinicalsignificanceanddosage

shouldbedeterminedbyseizurecontrol.Thevolumeofdistributionisincreasedintheelderlyandbecauseof

decreasedbindingtoserumalbumin,theproportionoffreedrugisincreased.Thiswillaffecttheclinicalinterpretation

ofplasmavalproicacidlevels.

Inpatientswithrenalinsufficiency

Itmaybenecessarytodecreasethedosage.Dosageshouldbeadjustedaccordingtoclinicalmonitoringsince

monitoringofplasmaconcentrationsmaybemisleading(seesection5.2PharmacokineticProperties).

CombinedTherapy

WhenstartingEpiliminpatientsalreadyonotheranticonvulsants,theseshouldbetaperedslowly:initiationofEpilim

therapyshouldthenbegradual,withtargetdosebeingreachedafterabout2weeks.Incertaincasesitmaybe

necessarytoraisethedoseby5to10mg/kg/daywhenusedincombinationwithanticonvulsantswhichinduceliver

enzymeactivity,e.g.phenytoin,phenobarbitalandcarbamazepine.Onceknownenzymeinducershavebeen

withdrawnitmaybepossibletomaintainseizurecontrolonareduceddoseofEpilim.Whenbarbituratesarebeing

administeredconcomitantlyandparticularlyifsedationisobserved(particularlyinchildren)thedosageofbarbiturate

shouldbereduced.

NB:Inchildrenrequiringdoseshigherthen40mg/kg/dayclinicalchemistryandhaematologicalparametersshouldbe

monitored.

Optimumdosageismainlydeterminedbyseizurecontrolandroutinemeasurementofplasmalevelsisunnecessary.

However,amethodformeasurementofplasmalevelsisavailableandmaybehelpfulwherethereispoorcontrolor

sideeffectsaresuspected(seesection5.2PharmacokineticProperties).

4.3Contraindications

-Activeliverdisease.

-Personalorfamilyhistoryofseverehepaticdysfunction,especiallydrugrelated.

-Hypersensitivitytosodiumvalproate.

-Porphyria.

4.4Specialwarningsandprecautionsforuse

Stoppingtreatmentmayleadtoanimmediaterelapseoftheunderlyingsymptoms;careshouldthereforebetakenwhen

considerationisbeinggiventothewithdrawaloftreatment.

Theconcomitantuseofvalproicacid/sodiumvalproateandcarbapenemagentsisnotrecommended(seesection4.5).

4.4.1SpecialWarnings

Liverdysfunction:

Conditionsofoccurrence:

Severeliverdamage,includinghepaticfailuresometimesresultinginfatalities,hasbeenexceptionallyreported.

Experienceinepilepsyhasindicatedthatpatientsmostatrisk,especiallyincasesofmultipleanticonvulsanttherapy,

areinfantsandinparticularyoungchildrenundertheageof3andthosewithsevereseizuredisorders,organicbrain

disease,and(or)congenitalmetabolicordegenerativediseaseassociatedwithmentalretardation.Aftertheageof3,the

incidenceofoccurrenceissignificantlyreducedandprogressivelydecreaseswithage.

Inmostcases,suchliverdamageoccurredduringthefirst6monthsoftherapy,theperiodofmaximumriskbeing2-12

weeks.

Suggestivesigns:

Clinicalsymptomsareessentialforearlydiagnosis.Inparticularthefollowingconditions,whichmayprecedejaundice,

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-nonspecificsymptoms,usuallyofsuddenonset,suchasasthenia,malaise,anorexia,lethargy,oedemaand

drowsiness,whicharesometimesassociatedwithrepeatedvomitingandabdominalpain.

-inpatientswithepilepsy,recurrenceofseizures.

Theseareanindicationforimmediatewithdrawalofthedrug.Patients(ortheirfamilyforchildren)shouldbe

instructedtoreportimmediatelyanysuchsignstoaphysicianshouldtheyoccur.Investigationsincludingclinical

examinationandbiologicalassessmentofliverfunctionshouldbeundertakenimmediately.

Detection:

Liverfunctionshouldbemeasuredbeforeandthenperiodicallymonitoredduringthefirst6monthsoftherapy,

especiallyinthosewhoseemmostatrisk,andthosewithapriorhistoryofliverdisease.Amongstusualinvestigations,

tests,whichreflectproteinsynthesis,particularlyprothrombinrate,aremostrelevant.Confirmationofanabnormally

lowprothrombinrate,particularlyinassociationwithotherbiologicalabnormalities(significantdecreaseinfibrinogen

andcoagulationfactors;increasedbilirubinlevelandraisedtransaminases)requirescessationofEpilimtherapy.Asa

matterofprecautionandincasetheyaretakenconcomitantlysalicylatesshouldalsobediscontinuedsincetheyemploy

thesamemetabolicpathway.

Pancreatitis:

Severepancreatitis,whichmayresultinfatalities,hasbeenveryrarelyreported.Patientsexperiencingacuteabdominal

painshouldhaveapromptmedicalevaluation.Youngchildrenareatparticularrisk;thisriskdecreaseswithincreasing

age.Severeseizuresandsevereneurologicalimpairmentwithcombinationanticonvulsanttherapymayberiskfactors.

Hepaticfailurewithpancreatitisincreasestheriskoffataloutcome.Incaseofpancreatitis,Epilimshouldbe

discontinued.

Womenofchildbearingpotential

AdecisiontouseEpiliminwomenofchildbearingpotentialshouldonlybetakenafterverycarefulevaluation,ifthe

benefitsofitsuseoutweightherisksofcongenitalanomaliestotheunbornchild.Thisdecisionistobetaken;before

Epilimisprescribedforthefirsttimeaswellasbeforeawomanalreadytreatedwithsodiumvalproateisplanninga

pregnancy.

Suicidalideationandbehaviour

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithantiepilepticagentsinseveralindications.A

meta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforvalproate.Thereforepatientsshouldbemonitoredforsignsofsuicidalideationand

behavioursandappropriatetreatmentshouldbeconsidered.Patients(andcaregiversofpatients)shouldbeadvisedto

seekmedicaladviceshouldsignsofsuicidalideationorbehaviouremerge.

4.4.2Precautions

Liverfunctiontestsshouldbecarriedoutbeforetherapy(seesection4.3Contraindications),andperiodicallyduringthe

first6months,especiallyinpatientsatrisk(seesection4.4.1Specialwarnings).

Aswithmostantiepilepticdrugs,increasedliverenzymesarecommon,particularlyatthebeginningoftherapy;they

arealsotransient.

Moreextensivebiologicalinvestigations(includingprothrombinrate)arerecommendedinthesepatients;areduction

indosagemaybeconsideredwhenappropriateandtestsshouldberepeatedasnecessary.

Children:Monotherapyisrecommendedinchildrenundertheageof3yearswhenprescribingEpilim,butthe

potentialbenefitofEpilimshouldbeweighedagainsttheriskofliverdamageorpancreatitisinsuchpatientspriorto

initiationoftherapy(seesection4.4.1Specialwarnings).

Theconcomitantuseofsalicylatesshouldbeavoidedinchildrenunder3duetotheriskoflivertoxicity.

Haematological:Bloodtests(bloodcellcount,includingplateletcount,bleedingtimeandcoagulationtests)are

recommendedpriortoinitiationoftherapyorbeforesurgery,andincaseofspontaneousbruisingorbleeding(see

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Renalinsufficiency:Inpatientswithrenalinsufficiency,itmaybenecessarytodecreasedosage.Asmonitoringof

plasmaconcentrationsmaybemisleading,dosageshouldbeadjustedaccordingtoclinicalmonitoring(seesections4.2

PosologyandMethodofAdministrationand5.2.PharmacokineticProperties).

Systemiclupuserythematosus:AlthoughimmunedisordershaveonlyrarelybeennotedduringtheuseofEpilim,the

potentialbenefitofEpilimshouldbeweighedagainstitsriskinpatientswithsystemiclupuserythematosus(seealso

section4.8UndesirableEffects).

Hyperammonaemia:Whenaureacycleenzymaticdeficiencyissuspected,metabolicinvestigationsshouldbe

performedpriortotreatmentbecauseoftheriskofhyperammonaemiawithEpilim.

Diabeticpatients:Epilimiseliminatedmainlythroughthekidneys,partlyintheformofketonebodies;thismaygive

falsepositivesintheurinetestingofpossiblediabetics.

Patientsshouldbewarnedoftheriskofweightgainattheinitiationoftherapy,andappropriatestrategiesshouldbe

adoptedtominimiseit(see4.8UndesirableEffects).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

4.5.1EffectsofEpilimonOtherDrugs

-Antipsychotics,MAOinhibitors,antidepressantsandbenzodiazepines

Epilimmaypotentiatetheeffectofotherpsychotropicssuchasantipsychotics,MAOinhibitors,antidepressantsand

benzodiazepines;therefore,clinicalmonitoringisadvisedandthedosageoftheotherpsychotropicsshouldbeadjusted

whenappropriate.

Inparticular,aclinicalstudyhassuggestedthataddingolanzapinetovalproatetherapymaysignificantlyincreasethe

riskofcertainadverseeventsassociatedwitholanzapine.

-Phenobarbital

Epilimincreasesphenobarbitalplasmaconcentrations(duetoinhibitionofhepaticcatabolism)andsedationmayoccur,

particularlyinchildren.Therefore,clinicalmonitoringisrecommendedthroughoutthefirst15daysofcombined

treatmentwithimmediatereductionofphenobarbitaldosesifsedationoccursanddeterminationofphenobarbital

plasmalevelswhenappropriate.

-Primidone

Epilimincreasesprimidoneplasmalevelswithexacerbationofitsadverseeffects(suchassedation);thesesignscease

withlongtermtreatment.Clinicalmonitoringisrecommendedespeciallyatthebeginningofcombinedtherapywith

dosageadjustmentwhenappropriate.

-Phenytoin

Epilimdecreasesphenytointotalplasmaconcentration.MoreoverEpilimincreasesphenytoinfreeformwithpossible

overdosagesymptoms(valproicaciddisplacesphenytoinfromitsplasmaproteinbindingsitesandreducesitshepatic

catabolism).Thereforeclinicalmonitoringisrecommended;whenphenytoinplasmalevelsaredetermined,thefree

formshouldbeevaluated.

-Carbamazepine

ClinicaltoxicityhasbeenreportedwhenEpilimwasadministeredwithcarbamazepineasEpilimmaypotentiatetoxic

effectsofcarbamazepine.Clinicalmonitoringisrecommendedespeciallyatthebeginningofcombinedtherapywith

dosageadjustmentwhenappropriate.

-Lamotrigine

Theriskofrashmaybeincreasedbyco-administrationoflamotriginewithvalproicacidwhenlamotrigineisaddedon

tovalproicacid.Epilimmayreducelamotriginemetabolismandincreaseitsmeanhalf-life,dosagesshouldbeadjusted

(lamotriginedosagedecreased)whenappropriate.

-Zidovudine

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-VitaminK-dependentanticoagulants

Theanticoagulanteffectofwarfarinandothercoumarinanticoagulantsmaybeincreasedfollowingdisplacementfrom

plasmaproteinbindingsitesbyvalproicacid.Theprothrombintimeshouldbecloselymonitored.

4.5.2EffectsofOtherDrugsonEpilim

Antiepilepticswithenzymeinducingeffect(includingphenytoin,phenobarbital,carbamazepine)decreasevalproic

acidplasmaconcentrations.Dosagesshouldbeadjustedaccordingtobloodlevelsincaseofcombinedtherapy.

Ontheotherhand,combinationoffelbamateandEpilimmayincreasevalproicacidplasmaconcentration.Epilim

dosageshouldbemonitored.

Mefloquineandchloroquineincreasevalproicacidmetabolismandhaveaconvulsingeffect.Theymaylowerthe

seizurethreshold;thereforeepilepticseizuresmayoccurincasesofcombinedtherapy.ThedosageofEpilimmayneed

adjustmentaccordingly.

IncaseofconcomitantuseofEpilimandhighlyproteinboundagents(e.g.aspirin),freevalproicacidplasmalevels

maybeincreased.

Valproicacidplasmalevelsmaybeincreased(asaresultofreducedhepaticmetabolism)incaseofconcomitantuse

withcimetidineorerythromycin.

Decreasesinbloodlevelsofvalproicacidhavebeenreportedwhenitisco-administeredwithcarbapenemagents

resultingina60-100%decreaseinvalproicacidlevelsinabouttwodays.Duetotherapidonsetandtheextentofthe

decrease,co-administrationofcarbapenemagentsinpatientsstabilisedonvalproicacidisnotconsideredtobe

manageableandthereforeshouldbeavoided(seesection4.4).

ColestyraminemaydecreasetheabsorptionofEpilim.

Rifampicinmaydecreasethevalproatebloodlevelsresultinginalackoftherapeuticeffect.Therefore,valproate

dosageadjustmentmaybenecessarywhenitisco-administeredwithrifampicin.

4.5.3OtherInteractions

CautionisadvisedwhenusingEpilimincombinationwithneweranti-epilepticswhosepharmacodynamicsmaynotbe

wellestablished.

Concomitantadministrationofvalproateandtopiramatehasbeenassociatedwithencephalopathyand/or

hyperammonemia.Patientstreatedwiththosetwodrugsshouldbecarefullymonitoredforsignsandsymptomsof

hyperammonemicencephalopathy.

Epilimusuallyhasnoenzyme-inducingeffect;asaconsequence,Epilimdoesnotreduceefficacyofoestroprogestative

agentsinwomenreceivinghormonalcontraception,includingtheoralcontraceptivepill.

4.6Fertility,pregnancyandlactation

IncertaincasesEpilimmaybeanappropriatechoiceforwomenofchildbearingpotential,providedthataninformed

choicehasbeenmade,basedonaverycarefulevaluation,bythepatienttogetherwithhertreatingphysician,ofall

relevantelements.

4.6.1Pregnancy

Fromexperienceintreatingmotherswithepilepsy,theriskassociatedwiththeuseofEpilimduringpregnancyhas

beendescribedasfollows:

-Riskassociatedwithseizures

Duringpregnancy,maternaltonicclonicseizuresandstatusepilepticuswithhypoxiacarryaparticularriskofdeathfor

motherandfortheunbornchild.

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Inanimals:teratogeniceffectshavebeendemonstratedinthemouse,ratandrabbit.

Thereisanimalexperimentalevidencethathighplasmapeaklevelsandthesizeofanindividualdoseareassociated

withneuraltubedefects.

Inhumans:Availabledatasuggestanincreasedincidenceofminorormajormalformationsincludingneuraltube

defects,craniofacialdefects,malformationofthelimbs,cardiovascularmalformationsandmultipleanomalies

involvingvariousbodysystemsinoffspringborntomotherswithepilepsytreatedwithvalproatewhencomparedtothe

incidenceforcertainotherantiepilepticdrugs.Epilimuseisassociatedwithneuraltubedefectssuchas

myelomeningoceleandspinabifida.Thefrequencyofthiseffectisestimatedtobe1to2%.Datasuggestthat

antiepilepticpolytherapyincludingEpiliminducesahigherteratogenicriskthanmonotherapywithvalproateonly.

Datahavesuggestedanassociationbetweenin-uteroEpilimexposureandtheriskofdevelopmentaldelayparticularly

ofverbalIQinchildrenborntomotherssufferingfromepilepsyandtreatedwithvalproate.

Developmentaldelayisfrequentlyassociatedwithmalformationsand/ordysmorphicfeatures.However,itisdifficult

toestablishcasualrelationshipinviewofpossibleconfoundingfactorssuchaslowmaternalorpaternalIQ,genetic,

socialandenvironmentalfactors,andpoormaternalseizurecontrolduringpregnancy.

Autismspectrumdisordershavealsobeenreportedinchildrenexposedtovalproateinutero.

-Inviewoftheabovedata

WomenofchildbearingpotentialshouldbeinformedoftherisksandbenefitsoftheuseofEpilimduringpregnancy.

Specialistadviceisrequiredandphysiciansarestronglyencouragedtodiscussreproductiveissueswiththeirpatients

beforeEpilimisprescribedforthefirsttimeorawomanalreadytreatedwithEpilimisplanningapregnancy.

Ifawomanplanspregnancy,thisprovidesanopportunitytoreviewtheneedforanti-epileptictreatment.If,furthertoa

carefulevaluationoftherisksandbenefits,Epilimtreatmentiscontinuedduringthepregnancy,itisrecommendedto

useEpilimindivideddosesoverthedayatthelowesteffectivedose.Theuseofprolongedreleaseformulationmaybe

preferabletoanyothertreatmentform.

Inaddition,ifappropriate,folatesupplementationshouldbestartedbeforepregnancyandatrelevantdosage(5mg

daily)asitmayminimizetheriskofneuraltubedefects.

Duringpregnancy,Epilimanti-epileptictreatmentshouldnotbediscontinuedwithoutreassessmentofthebenefit/risk.

Specialisedprenatalmonitoringshouldbeinstitutedinordertodetectthepossibleoccurrenceofaneuraltubedefector

anyothermalformation.Pregnanciesshouldbecarefullyscreenedbyultrasound,andothertechniquesifappropriate

(seeSection4.4SpecialWarningsandSpecialPrecautionsforuse).

-Riskintheneonate

Veryrarecasesofhaemorrhagicsyndromehavebeenreportedinneonateswhosemothershavetakenvalproateduring

pregnancy.Thishaemorrhagicsyndromeisrelatedtohypofibrinogenemia;afibrinogenemiahasalsobeenreportedand

maybefatal.Thesearepossiblyassociatedwithadecreaseofcoagulationfactors.However,thissyndromehastobe

distinguishedfromthedecreaseofthevitamin-Kfactorsinducedbyphenobarbitalandotheranti-epilepticenzyme

inducingdrugs.

Therefore,plateletcount,fibrinogenplasmalevel,coagulationtestsandcoagulationfactorsshouldbeinvestigatedin

neonates.

4.6.2Lactation

ExcretionofEpiliminbreastmilkislow,withaconcentrationbetween1%to10%oftotalmaternalserumlevels.

Basedonliteratureandclinicalexperience,breastfeedingcanbeenvisaged,takingintoaccounttheEpilimsafety

profile,especiallyhaematologicaldisorders(seesection4.8UndesirableEffects).

4.7Effectsonabilitytodriveandusemachines

UseofEpilimmayprovideseizurecontrolsuchthatthepatientmaybeeligibletoholdadrivinglicence.

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associationwithbenzodiazepines(Seebelowand4.5,Interactionwithothermedicinalproductsandotherformsof

interactions).

4.8Undesirableeffects

Congenitalandfamilial/geneticdisorders:(seesection4.6.PregnancyandLactation).

Hepato-biliarydisorders:rarecasesofliverinjury(seesection4.4.1.Specialwarnings).

Gastrointestinaldisorders:(nausea,abdominalpainupper,diarrhoea)frequentlyoccuratthestartoftreatment,but

theyusuallydisappearafterafewdayswithoutdiscontinuingtreatment.Theseproblemscanusuallybeovercomeby

takingEpilimwithorafterfoodorbyusingEntericCoatedEpilim.

Veryrarecasesofpancreatitis,sometimeslethal,havebeenreported(seesection4.4SpecialWarningsandSpecial

PrecautionsforUse).

Nervoussystemdisorders:Sedationhasbeenreportedoccasionally,usuallywhenincombinationwithother

anticonvulsants.Inmonotherapyithasoccurredearlyintreatmentonrareoccasionsandisusuallytransient.Rarecases

oflethargyandconfusion,occasionallyprogressingtostupor,sometimeswithassociatedhallucinationsorconvulsions

havebeenreported.Encephalopathyandcomahaveveryrarelybeenobserved.Thesecaseshaveoftenbeenassociated

withtoohighastartingdoseortoorapidadoseescalationorconcomitantuseofotheranticonvulsants,notably

phenobarbitalortopiramate.Theyhaveusuallybeenreversibleonwithdrawaloftreatmentorreductionofdosage.

Veryrarecasesofreversibleparkinsonism,orreversibledementiaassociatedwithreversiblecerebralatrophyhave

beenreported.Ataxiaandtransientand/ordoserelatedfineposturaltremorhaveoccasionallybeenreported.

Anincreaseinalertnessmayoccur;thisisgenerallybeneficialbutoccasionallyaggression,hyperactivityand

behaviouraldeteriorationhavebeenreported.

Casesofisolatedandmoderatehyperammonaemiawithoutchangeinliverfunctionmayoccurfrequentlyandshould

notcausetreatmentdiscontinuation.However,theymaypresentclinicallyasvomiting,ataxia,andincreasingclouding

ofconsciousness.ShouldthesesymptomsoccurEpilimshouldbediscontinued.

Hyperammonaemiaassociatedwithneurologicalsymptomshasalsobeenreported(seesection4.4.2Precautions).In

suchcasesfurtherinvestigationsshouldbeconsidered.

Metabolicandnutritiondisorders:

Veryrarecasesofhyponatremiahavebeenreported.

SyndromeofInappropriateSecretionofADH(SIADH)

Bloodandlymphaticsystemdisorders:

Frequentoccurrenceofthrombocytopenia,rarecasesofanaemia,leucopoeniaorpancytopenia.Thebloodpicture

returnedtonormalwhenthedrugwasdiscontinued.

Bonemarrowfailure,includingpreredcellaplasia.Agranulocytosis.Isolatedfindingsofareductioninblood

fibrinogenand/orincreaseinprothrombintimehavebeenreported,usuallywithoutassociatedclinicalsignsand

particularlywithhighdoses(Epilimhasaninhibitoryeffectonthesecondphaseofplateletaggregation).Spontaneous

bruisingorbleedingisanindicationforwithdrawalofmedicationpendinginvestigations(seealsosection4.6

PregnancyandLactation)

Skinandsubcutaneoustissuedisorders:

Veryrare:toxicepidermalnecrolysis,Stevens-Johnsonsyndrome,anderythemamultiforme,rash.

Transientand/ordoserelatedalopecia,hasoftenbeenreported.Regrowthnormallybeginswithinsixmonths,although

thehairmaybecomemorecurlythanpreviously.

Reproductivesystemandbreastdisorders:

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Vasculardisorders:

Theoccurrenceofvasculitishasoccasionallybeenreported.

Earandlabyrinthdisorders:

Deafness,eitherreversibleorirreversiblehasbeenreportedrarely.

Renalandurinarydisorders:

TherehavebeenisolatedreportsofareversibleFanconi'ssyndrome(adefectinproximalrenaltubularfunctiongiving

risetoglycosuria,aminoaciduria,phosphaturia,anduricosuria),butthemodeofactionisasyetunclear.

Veryrarecasesofenuresishavebeenreported.

Immunesystemdisorders:

Angioedema,DrugRashwithEosinophiliaandSystemicSymptoms(DRESS)syndrome.Allergicreactions(ranging

fromrashtohypersensitivityreactions)havebeenreported.

Psychiatricdisorders:

Confusion

Generaldisordersandadministrationsiteconditions:

Veryrarecasesofnon-severeperipheraloedemahavebeenreported.

Increaseinweightmayalsooccur.Sinceitisariskfactorforpolycysticovarysyndrome,itshouldbecarefully

monitored(seesection4.4SpecialWarningsandSpecialPrecautionsforUse).

4.9Overdose

CasesofaccidentalanddeliberateEpilimoverdosagehavebeenreported.Atplasmaconcentrationsofupto5to6

timesthemaximumtherapeuticlevels,thereareunlikelytobeanysymptomsotherthannausea,vomitingand

dizziness.

Signsofmassiveoverdose,i.e.plasmaconcentration10to20timesmaximumtherapeuticlevels,usuallyincludeCNS

depressionorcomawithmuscularhypotonia,hyporeflexia,miosis,impairedrespiratoryfunction,metabolicacidosis.

Deathshaveoccurredfollowingmassiveoverdose;nevertheless,afavourableoutcomeisusual.

Symptomsmayhoweverbevariableandseizureshavebeenreportedinthepresenceofveryhighplasmalevels(see

alsosection5.2PharmacokineticProperties).Casesofintracranialhypertensionrelatedtocerebraloedemahavebeen

reported.

Hospitalmanagementofoverdoseshouldbesymptomatic:gastriclavage,cardio-respiratorymonitoringHaemodialysis

andhaemoperfusionhavebeenusedsuccessfully.

Naloxonehasalsobeenusedinafewisolatedcases.Incasesofmassiveoverdose,hemodialysisandhemoperfusion

havebeenusedsuccessfully.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Sodiumvalproateisananticonvulsant.

ThemostlikelymodeofactionforEpilimispotentiationoftheinhibitoryactionofgammaamino-butyricacid

(GABA)throughanactiononthefurthersynthesisorfurthermetabolismofGABA.

Incertaininvitrostudies,ithasbeenreportedthatEpilimcanstimulateHIV.Howeverthiseffectismodest,variable,

unrelatedtothedoseandnotdocumentedinman.

5.2Pharmacokineticproperties

Thehalf-lifeofEpilimisusuallyreportedtobewithintherange8-20hours.Itisusuallyshorterinchildren.

Thereportedeffectivetherapeuticrangeforplasmavalproicacidlevelsis40-100mg/litre(278-694micromol/litre).

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drugisusuallybetween6%and15%ofthetotalplasmalevels.Anincreasedincidenceofadverseeffectsmayoccur

withplasmalevelsabovetheeffectivetherapeuticrange.

Thepharmacological(ortherapeutic)effectsofEpilimmaynotbeclearlycorrelatedwiththetotalorfree(unbound)

plasmavalproicacidlevels.

5.3Preclinicalsafetydata

Therearenopreclinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedinother

sectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Povidone

Talc

MagnesiumStearate

CalciumSilicate

Polyvinylacetatephthalate

Citricacid

Hypromellose

Macrogol6000

VioletLakeSolidscontaining:

TitaniumDioxide(E171)

AmaranthLake(E123)

Indigocarminelake(E132)

Hydroxypropylcellulose

DiethylPhthalate

Stearicacid

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductisthedateshownontheblisterandouterpackageoftheproductasmarketed

inthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

Storeintheoriginalpackage

Storeinadryplace

Patientsshouldbeadvisedtoleavethetabletsinthefoiluntiljustbeforetakingthem

6.5Natureandcontentsofcontainer

Cardboardoutercontainingblisterstrips.Eachblisterstripcontains10tablets.

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLimited

UnitL2

NorthRingBusinessPark

Santry

Dublin9

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1151/117/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:31stJuly2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 31/05/2011 CRN 2100682 page number: 10