EPI-CHRONO 200 MG PROLONGED-RELEASE TABLETS

Main information

  • Trade name:
  • EPI-CHRONO 200 MG PROLONGED-RELEASE TABLETS
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Prolonged Release Capsules
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPI-CHRONO 200 MG PROLONGED-RELEASE TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0540/149/001
  • Authorization date:
  • 07-12-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0540/149/001

CaseNo:2081454

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Sanofi-aventisIrelandLimited

CitywestBusinessCampus,Dublin24,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Epi-Chrono200mgProlonged-ReleaseTablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom13/07/2010until23/08/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epi-Chrono200mgProlonged-ReleaseTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachEpichrono200mgprolonged-releasetabletcontains133.2mgsodiumvalproateand58.0mgvalproicacid,

equivalentto200mgsodiumvalproate.

Thisproductcontains18.4mgofsodium.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet.

Violet,oblong,biconvex,film-coatedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inthetreatmentofgeneralised,partialorotherepilepsy.

IncertaincasesEpiChronomaybeanappropriatechoiceforwomenofchildbearing

potential,providedthataninformedchoicehasbeenmade,basedonaverycareful

evaluation,bythepatienttogetherwithhertreatingphysician,ofallrelevantelements(see

4.6PregnancyandLactation).

4.2Posologyandmethodofadministration

EpiChronoProlongedReleaseTabletsarefororaladministration.

EpiChronoisaprolongedreleaseformulationwhichreducespeakconcentrationandensuresmoreevenplasma

concentrationsthroughouttheday.

EpiChronomaybegivenonceortwicedaily.Thetabletsshouldbeswallowedwholeandnotcrushedorchewed.

Dailydosagerequirementsvaryaccordingtoageandbodyweight.

InpatientswhereadequatecontrolhasbeenachievedEpiChronoformulationsareinterchangeablewithotherEpilim

conventionalorprolongedreleaseformulationsonanequivalentdailydosagebasis.

Dosage

Usualrequirementsareasfollows:

Adults

Dosageshouldstartat600mgdailyincreasingby200mgatthree-dayintervalsuntilcontrolisachieved.Thisis

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

controlisnotachievedwithinthisrangethedosemaybefurtherincreasedto2500mgperday.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 2

Initialdosageshouldbe400mg/day(irrespectiveofweight)withspacedincreasesuntilcontrolisachieved;thisis

usuallywithintherange20-30mg/kgbodyweightperday.Whereadequatecontrolisnotachievedwithinthisrange

thedosemaybeincreasedto35mg/kgbodyweightperday.

Childrenunder20kg

AnalternativeformulationofEpilimshouldbeusedinthisgroupofpatients,duetothetabletsizeandneedfordose

titration.EpilimLiquid(sugar-free)orEpilimSyruparealternatives.

Elderly

AlthoughthepharmacokineticsofEpiChronoaremodifiedintheelderly,theyhavelimitedClinicalsignificanceand

dosageshouldbedeterminedbyseizurecontrol.Thevolumeofdistributionisincreasedintheelderlyandbecauseof

decreasedbindingtoserumalbumin,theproportionoffreedrugisincreased.Thiswillaffecttheclinicalinterpretation

ofplasmavalproicacidlevels.

Inpatientswithrenalinsufficiency

Itmaybenecessarytodecreasethedosage.Dosageshouldbeadjustedaccordingtoclinicalmonitoringsince

monitoringofplasmaconcentrationsmaybemisleading(seesection5.2PharmacokineticProperties).

CombinedTherapy

WhenstartingEpiChronoinpatientsalreadyonotheranticonvulsants,theseshouldbetaperedslowly,initiationof

EpiChronotherapyshouldthenbegradual,withtargetdosebeingreachedafterabout2weeks.Incertaincasesitmay

benecessarytoraisethedoseby5to10mg/kg/daywhenusedincombinationwithanticonvulsantswhichinduceliver

enzymeactivity,e.g.phenytoin,Phenobarbitalandcarbamazepine.Onceknownenzymeinducershavebeenwithdrawn

itmaybepossibletomaintainseizurecontrolonareduceddoseofEpiChrono.Whenbarbituratesarebeing

administeredconcomitantlyandparticularlyifsedationisobserved(particularlyinchildren)thedosageofbarbiturate

shouldbereduced.

NB:Inchildrenrequiringdoseshigherthan40mg/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)

4.4.1 Specialwarnings

Liverdysfunction:

Conditionsofoccurrence:

Severeliverdamage,includinghepaticfailuresometimesresultinginfatalities,hasbeenexceptionallyreported.

Experienceinepilepsyhasindicatedthatpatientsmostatrisk,especiallyincasesofmultipleanticonvulsanttherapy,

areinfantsandinparticularyoungchildrenundertheageof3andthosewithsevereseizuredisorders,organicbrain

disease,and(or)congenitalmetabolicordegenerativediseaseassociatedwithmentalretardation.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 3

Inmostcases,suchliverdamageoccurredduringthefirst6monthsoftherapy,theperiodofmaximumriskbeing2-12

weeks.

Suggestivesigns:

Clinicalsymptomsareessentialforearlydiagnosis.Inparticular,thefollowingconditions,whichmayprecede

jaundice,shouldbetakenintoconsideration,especiallyinpatientsatrisk(seeabove:‘Conditionsofoccurrence’):

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

drowsiness,whicharesometimesassociatedwithrepeatedvomitingandabdominalpain.

-inpatientswithepilepsy,recurrenceofseizures.

Theseareanindicationforimmediatewithdrawalofthedrug.

Patients(ortheirfamilyforchildren)shouldbeinstructedtoreportimmediatelyanysuchsignstoaphysicianshould

theyoccur.Investigationsincludingclinicalexaminationandbiologicalassessmentofliverfunctionshouldbe

undertakenimmediately.

Detection:

Liverfunctionshouldbemeasuredbeforeandthenperiodicallymonitoredduringthefirst6monthsoftherapy,

especiallyinthosewhoseemmostatrisk,andthosewithapriorhistoryofliverdisease.

Amongstusualinvestigations,testswhichreflectproteinsynthesis,particularlyprothrombinrate,aremostrelevant.

Confirmationofanabnormallylowprothrombinrate,particularlyinassociationwithotherbiologicalabnormalities

(significantdecreaseinfibrinogenandcoagulationfactors;increasedbilirubinlevelandraisedtransaminases)requires

cessationofEpiChronotherapy.

Asamatterofprecautionandincasetheyaretakenconcomitantlysalicylatesshouldalsobediscontinuedsincethey

employthesamemetabolicpathway.

Pancreatitis:Severepancreatitis,whichmayresultinfatalities,hasbeenveryrarelyreported.Patientsexperiencing

acuteabdominalpainshouldhaveapromptmedicalevaluation.Youngchildrenareatparticularrisk;thisrisk

decreaseswithincreasingage.Severeseizuresandsevereneurologicalimpairmentwithcombinationanticonvulsant

therapymayberiskfactors.Hepaticfailurewithpancreatitisincreasestheriskoffataloutcome.Incaseofpancreatitis,

EpiChronoshouldbediscontinued.

Womenofchildbearingpotential

AdecisiontouseEpiChronoinwomenofchildbearingpotentialshouldonlybetakenafterverycarefulevaluation,if

thebenefitsofitsuseoutweightherisksofcongenitalanomaliestotheunbornchild.Thisdecisionistobetaken;

beforeEpiChronoisprescribedforthefirsttimeaswellasbeforeawomanalreadytreatedwithsodiumvalproateis

planningapregnancy.

Suicidalideationandbehaviour

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithantiepilepticagentsinseveralindications.A

meta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforvalproate.Thereforepatientsshouldbemonitoredforsignsofsuicidalideationand

behavioursandappropriatetreatmentshouldbeconsidered.Patients(andcaregiversofpatients)shouldbeadvisedto

seekmedicaladviceshouldsignsofsuicidalideationorbehaviouremerge.

4.4.2 Precautions

Liverfunctiontestsshouldbecarriedoutbeforetherapy(seesection4.3Contraindications),andperiodicallyduringthe

first6months,especiallyinpatientsatrisk(seesection4.4.1Specialwarnings).

Aswithmostantiepilepticdrugs,increasedliverenzymesarecommon,particularlyatthebeginningoftherapy;they

arealsotransient.Moreextensivebiologicalinvestigations(includingprothrombinrate)arerecommendedinthese

patients;areductionindosagemaybeconsideredwhenappropriateandtestsshouldberepeatedasnecessary.

Children:Monotherapyisrecommendedinchildrenundertheageof3yearswhenprescribingEpiChrono,butthe

potentialbenefitofEpiChronoshouldbeweighedagainsttheriskofliverdamageorpancreatitisinsuchpatientsprior

toinitiationoftherapy(seesection4.4.1Specialwarnings).

Theconcomitantuseofsalicylatesshouldbeavoidedinchildrenunder3duetotheriskoflivertoxicity.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 4

recommendedpriortoinitiationoftherapyorbeforesurgery,andincaseofspontaneousbruisingorbleeding(see

section4.8UndesirableEffects).

Renalinsufficiency:Inpatientswithrenalinsufficiency,itmaybenecessarytodecreasedosage.Asmonitoringof

plasmaconcentrationsmaybemisleading,dosageshouldbeadjustedaccordingtoclinicalmonitoring(seesections4.2

PosologyandMethodofAdministrationand5.2.PharmacokineticProperties).

Systemiclupuserythematosus:AlthoughimmunedisordershaveonlyrarelybeennotedduringtheuseofEpiChrono,

thepotentialbenefitofEpiChronoshouldbeweighedagainstitsriskinpatientswithsystemiclupuserythematosus(see

alsosection4.8UndesirableEffects).

Hyperammonaemia:Whenaureacycleenzymaticdeficiencyissuspected,metabolicinvestigationsshouldbe

performedpriortotreatmentbecauseoftheriskofhyperammonaemiawithEpiChrono.

Diabeticpatients:EpiChronoiseliminatedmainlythroughthekidneys,partlyintheformofketonebodies;thismay

givefalsepositivesintheurinetestingofpossiblediabetics.

Patientsshouldbewarnedoftheriskofweightgainattheinitiationoftherapyandappropriatestrategiesshouldbe

adoptedtominimiseit(see4.8UndesirableEffects).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

4.5.1 EffectsofEpiChronoonOtherDrugs

-Antipsychotics,MAOinhibitors,antidepressantsandbenzodiazepinesEpiChronomaypotentiatetheeffectofother

psychotropicssuchasantipsychotics,MAOinhibitors,antidepressantsandbenzodiazepines;therefore,clinical

monitoringisadvisedandthedosageoftheotherpsychotropicsshouldbeadjustedwhenappropriate.Inparticular,a

clinicalstudyhassuggestedthataddingolanzapinetovalproatetherapymaysignificantlyincreasetheriskofcertain

adverseeventsassociatedwitholanzapine.

-Phenobarbital

EpiChronoincreasesphenobarbitalplasmaconcentrations(duetoinhibitionofhepaticcatabolism)andsedationmay

occur,particularlyinchildren.Therefore,clinicalmonitoringisrecommendedthroughoutthefirst15daysofcombined

treatmentwithimmediatereductionofphenobarbitaldosesifsedationoccursanddeterminationofphenobarbital

plasmalevelswhenappropriate.

-Primidone

EpiChronoincreasesprimidoneplasmalevelswithexacerbationofitsadverseeffects(suchassedation);thesesigns

ceasewithlongtermtreatment.Clinicalmonitoringisrecommendedespeciallyatthebeginningofcombinedtherapy

withdosageadjustmentwhenappropriate.

-Phenytoin

EpiChronodecreasesphenytointotalplasmaconcentration.MoreoverEpiChronoincreasesphenytoinfreeformwith

possibleoverdosagesymptoms(valproicaciddisplacesphenytoinfromitsplasmaproteinbindingsitesandreducesits

hepaticcatabolism).Thereforeclinicalmonitoringisrecommended;whenphenytoinplasmalevelsaredetermined,the

freeformshouldbeevaluated.

-Carbamazepine

ClinicaltoxicityhasbeenreportedwhenEpiChronowasadministeredwithcarbamazepineasEpiChronomay

potentiatetoxiceffectsofcarbamazepine.Clinicalmonitoringisrecommendedespeciallyatthebeginningofcombined

therapywithdosageadjustmentwhenappropriate.

-Lamotrigine

Theriskofrashmaybeincreasedbyco-administrationoflamotriginewithvalproicacidwhenlamotrigineisaddedon

tovalproicacid.EpiChronomayreducelamotriginemetabolismandincreaseitsmeanhalf-life,dosagesshouldbe

adjusted(lamotriginedosagedecreased)whenappropriate.

-Zidovudine

EpiChronomayraisezidovudineplasmaconcentrationleadingtoincreasedzidovudinetoxicity.

-VitaminK-dependentanticoagulants

Theanticoagulanteffectofwarfarinandothercoumarinanticoagulantsmaybeincreasedfollowingdisplacementfrom

plasmaproteinbindingsitesbyvalproicacid.Theprothrombintimeshouldbecloselymonitored.

4.5.2 EffectsofOtherDrugsonEpiChrono

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 5

acidplasmaconcentrations.Dosagesshouldbeadjustedaccordingtobloodlevelsincaseofcombinedtherapy.

Ontheotherhand,combinationoffelbamateandEpiChronomayincreasevalproicacidplasmaconcentration.

EpiChronodosageshouldbemonitored.

Mefloquineandchloroquineincreasevalproicacidmetabolismandhaveaconvulsingeffect.Theymaylowerthe

seizurethreshold;thereforeepilepticseizuresmayoccurincasesofcombinedtherapy.ThedosageofEpiChronomay

needadjustmentaccordingly.

IncaseofconcomitantuseofEpiChronoandhighlyproteinboundagents(e.g.aspirin),freevalproicacidplasma

levelsmaybeincreased.

Valproicacidplasmalevelsmaybeincreased(asaresultofreducedhepaticmetabolism)incaseofconcomitantuse

withcimetidineorerythromycin.

Decreasesinbloodlevelsofvalproicacidhavebeenreportedwhenitisco-administeredwithcarbapenemagents

resultingina60-100%decreaseinvalproicacidlevelsinabouttwodays.Duetotherapidonsetandtheextentofthe

decrease,co-administrationofcarbapenemagentsinpatientsstabilisedonvalproicacidisnotconsideredtobe

manageableandthereforeshouldbeavoided(seesection4.4)

ColestyraminemaydecreasetheabsorptionofEpiChrono.

Rifampicinmaydecreasethevalproatebloodlevelsresultinginalackoftherapeuticeffect.Therefore,valproate

dosageadjustmentmaybenecessarywhenitisco-administeredwithrifampicin.

4.5.3 OtherInteractions

CautionisadvisedwhenusingEpiChronoincombinationwithneweranti-epilepticswhosepharmacodynamicsmay

notbewellestablished.

Concomitantadministrationofvalproateandtopiramatehasbeenassociatedwithencephalopathyand/or

hyperammonemia.Patientstreatedwiththosetwodrugsshouldbecarefullymonitoredforsignsandsymptomsof

hyperammonemicencephalopathy.

EpiChronousuallyhasnoenzyme-inducingeffect;asaconsequence,EpiChronodoesnotreduceefficacyof

oestroprogestativeagentsinwomenreceivinghormonalcontraception,includingtheoralcontraceptivepill.

4.6Pregnancyandlactation

IncertaincasesEpiChronomaybeanappropriatechoiceforwomenofchildbearingpotential,providedthatan

informedchoicehasbeenmade,basedonaverycarefulevaluation,bythepatienttogetherwithhertreatingphysician,

ofallrelevantelements.

4.6.1 Pregnancy

Fromexperienceintreatingmotherswithepilepsy,theriskassociatedwiththeuseofEpiChronoduringpregnancyhas

beendescribedasfollows:

-Riskassociatedwithseizures

Duringpregnancy,maternaltonicclonicseizuresandstatusepilepticuswithhypoxiacarryaparticularriskofdeathfor

motherandfortheunbornchild.

-RiskassociatedwithEpiChrono

Inanimals:teratogeniceffectshavebeendemonstratedinthemouse,ratandrabbit.

Thereisanimalexperimentalevidencethathighplasmapeaklevelsandthesizeofanindividualdoseareassociated

withneuraltubedefects.

Inhumans:Availabledatasuggestanincreasedincidenceofminorormajormalformationsincludingneuraltube

defects,craniofacialdefects,malformationofthelimbs,cardiovascularmalformationsandmultipleanomalies

involvingvariousbodysystemsinoffspringborntomotherswithepilepsytreatedwithvalproatewhencomparedtothe

incidenceforcertainotherantiepilepticdrugs.EpiChronouseisassociatedwithneuraltubedefectssuchas

myelomeningoceleandspinabifida.Thefrequencyofthiseffectisestimatedtobe1to2%.

DatasuggestthatantiepilepticpolytherapyincludingEpiChronoinducesahigherteratogenicriskthanmonotherapy

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 6

developmentaldelayparticularlyofverbalIQinchildrenborntomotherssufferingfromepilepsyandtreatedwith

valproate.Developmentaldelayisfrequentlyassociatedwithmalformationsand/ordysmorphicfeatures.However,itis

difficulttoestablishcausalrelationshipinviewofpossibleconfoundingfactorssuchaslowmaternalorpaternalIQ,

genetic,socialandenvironmentalfactors,andpoormaternalseizurecontrolduringpregnancy.

Autismspectrumdisordershavealsobeenreportedinchildrenexposedtovalproateinutero.

-Inviewoftheabovedata

WomenofchildbearingpotentialshouldbeinformedoftherisksandbenefitsoftheuseofEpiChronoduring

pregnancy.Specialistadviceisrequiredandphysiciansarestronglyencouragedtodiscussreproductiveissueswith

theirpatientsbeforeEpiChronoisprescribedforthefirsttimeorawomanalreadytreatedwithEpiChronoisplanninga

pregnancy.

Ifawomanplanspregnancy,thisprovidesanopportunitytoreviewtheneedforanti-epileptictreatmentwhateverthe

indication.Inbipolardisordersindication,cessationofEpiChronoprophylaxisshouldbeconsidered.If,inany

indication,furthertoacarefulevaluationoftherisksandbenefits,EpiChronotreatmentiscontinuedduringthe

pregnancy,itisrecommendedtouseEpiChronoindivideddosesoverthedayatthelowesteffectivedose.Theuseof

prolongedreleaseformulationmaybepreferabletoanyothertreatmentform.

Inaddition,ifappropriate,folatesupplementationshouldbestartedbeforepregnancyandatrelevantdosage(5mg

daily)asitmayminimizetheriskofneuraltubedefects.

Duringpregnancy,EpiChronoanti-epileptictreatmentshouldnotbediscontinuedwithoutreassessmentofthe

benefit/risk.

Specialisedprenatalmonitoringshouldbeinstitutedinordertodetectthepossibleoccurrenceofaneuraltubedefector

anyothermalformations.Pregnanciesshouldbecarefullyscreenedbyultrasound,andothertechniquesifappropriate

(seeSection4.4SpecialWarningsandSpecialPrecautionsforuse).

-Riskintheneonate

Veryrarecasesofhaemorrhagicsyndromehavebeenreportedinneonateswhosemothershavetakenvalproateduring

pregnancy.Thishaemorrhagicsyndromeisrelatedtohypofibrinogenemia;afibrinogenemiahasalsobeenreportedand

maybefatal.Thesearepossiblyassociatedwithadecreaseofcoagulationfactors.However,thissyndromehastobe

distinguishedfromthedecreaseofthevitamin-Kfactorsinducedbyphenobarbitalandotheranti-epilepticenzyme

inducingdrugs.

Therefore,plateletcount,fibrinogenplasmalevel,coagulationtestsandcoagulationfactorsshouldbeinvestigatedin

neonates.

4.6.2 Lactation

ExcretionofEpiChronoinbreastmilkislow,withaconcentrationbetween1%to10%oftotalmaternalserumlevels.

Basedonliteratureandclinicalexperience,breastfeedingcanbeenvisaged,takingintoaccounttheEpiChronosafety

profile,especiallyhaematologicaldisorders(seesection4.8UndesirableEffects).

4.7Effectsonabilitytodriveandusemachines

UseofEpiChronomayprovideseizurecontrolsuchthatthepatientmaybeeligibletoholdadrivinglicence.

Patientsshouldbewarnedoftheriskoftransientdrowsiness,especiallyincasesofanticonvulsantpolytherapyor

associationwithbenzodiazepines(seesection4.5InteractionswithOtherMedicamentsandOtherFormsof

Interaction).

4.8Undesirableeffects

Congenital,familialandgeneticdisorders:(seesection4.6.PregnancyandLactation)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 7

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

usuallydisappearafterafewdayswithoutdiscontinuingtreatment.Theseproblemscanusuallybeovercomebytaking

EpiChronowithorafterfoodorbyusingEntericCoatedEpilim.

Veryrarecasesofpancreatitis,sometimeslethal,havebeenreported(seesection4.4SpecialWarningsandSpecial

PrecautionsforUse).

Nervoussystemdisorders:Sedationhasbeenreportedoccasionally,usuallywhenincombinationwithother

anticonvulsants.Inmonotherapyitoccurredearlyintreatmentonrareoccasionsandisusuallytransient.Rarecasesof

lethargyandconfusion,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.ShouldthesesymptomsoccurEpiChronoshouldbediscontinued.

Hyperammonaemiaassociatedwithneurologicalsymptomshasalsobeenreported(seesection4.4.2Precautions).In

suchcasesfurtherinvestigationsshouldbeconsidered.

Metabolicandnutritiondisorders:

Veryrarecasesofhyponatremiahavebeenreported.

SyndromeofInappropriateSecretionofADH(SIADH)

Bloodandlymphaticsystemdisorders:

Frequentoccurrenceofthrombocytopenia,rarecasesofanaemia,leucopoeniaorpancytopenia.Thebloodpicture

returnedtonormalwhenthedrugwasdiscontinued.

Bonemarrowfailure,includingpureredcellaplasia.Agranulocytosis.Isolatedfindingsofareductioninblood

fibrinogenand/orincreaseinprothrombintimehavebeenreported,usuallywithoutassociatedclinicalsignsand

particularlywithhighdoses(EpiChronohasaninhibitoryeffectonthesecondphaseofplateletaggregation).

Spontaneousbruisingorbleedingisanindicationforwithdrawalofmedicationpendinginvestigations(seealsosection

4.6PregnancyandLactation).

Skinandsubcutaneoustissuedisorders:

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

Transientand/ordoserelatedalopecia,hasoftenbeenreported.Regrowthnormallybeginswithinsixmonths,although

thehairmaybecomemorecurlythanpreviously.

Reproductivesystemandbreastdisorders:

Amenorrhoeaanddysmenorrheahavebeenreported.Veryrarelygynaecomastiahasoccurred.

Vasculardisorders:

Theoccurrenceofvasculitishasoccasionallybeenreported.

Earandlabyrinthdisorders:

Deafness,eitherreversibleorirreversiblehasbeenreportedrarely.

Renalandurinarydisorders:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 8

risetoglycosuria,aminoaciduria,phosphaturia,anduricosuria)butthemodeofactionisasyetunclear.

Veryrarecasesofenuresishavebeenreported.

Immunesystemdisorders:

Angioedema,DrugRashwithEosinophiliaandSystemicSymptoms(DRESS)syndrome.

Allergicreactions(rangingfromrashtohypersensitivityreactions)havebeenreported.

Psychiatricdisorders:

Confusion

Generaldisordersandadministrationsiteconditions:

Veryrarecasesofnon-severeperipheraloedemahavebeenreported.

Increaseinweightmayalsooccur.Sinceitisariskfactorforpolycysticovarysyndrome,itshouldbecarefully

monitored(seesection4.4SpecialWarningsandSpecialPrecautionsforUse).

4.9Overdose

CasesofaccidentalanddeliberateEpiChronooverdosagehavebeenreported.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-respiratorymonitoring.

Haemodialysisandhaemoperfusionhavebeenusedsuccessfully.

Naloxonehasalsobeenusedinafewisolatedcases.Incasesofmassiveoverdose,hemodialysisandhemoperfusion

havebeenusedsuccessfully.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Valproicacidandsodiumvalproateareanticonvulsants.

ThemostlikelymodeofactionforEpiChronoispotentiationoftheinhibitoryactionofgammaaminobutyricacid

(GABA)throughanactiononthefurthersynthesisorfurthermetabolismofGABA.

Incertaininvitrostudies,ithasbeenreportedthatEpiChronocanstimulateHIV.

Howeverthiseffectismodest,variable,unrelatedtothedoseandnotdocumentedinman.

5.2Pharmacokineticproperties

Thehalf-lifeofEpiChronoisusuallyreportedtobewithintherangeof8-20hours.Itis

usuallyshorterinchildren.

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

Thisreportedrangemaydependontimeofsamplingandpresenceofco-medication.Thepercentageoffree(unbound)

drugisusuallybetween6%and15%oftotalplasmalevels.Anincreasedincidenceofadverseeffectsmayoccurwith

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 9

Thepharmacological(ortherapeutic)effectsofEpiChronomaynotbeclearlycorrelated

withthetotalorfree(unbound)plasmavalproicacidlevels.

EpiChronoformulationsareprolongedreleaseformulationswhichdemonstrate

Inpharmacokineticstudieslessfluctuationinplasmaconcentrationcomparedwith

otherestablishedconventionalandprolongedreleaseEpilimformulations.

Incaseswheremeasurementofplasmalevelsisconsiderednecessary,thepharmacokinetics

ofEpiChronomakethemeasurementofplasmalevelslessdependentupontimeof

sampling.

TheEpiChronoformulationsarebioequivalenttoEpilimLiquidandEntericCoated(EC)

formulationswithrespecttothemeanareasundertheplasmaconcentrationtimecurves.

Steady-statepharmacokineticdataindicatethatthepeakconcentration(Cmax)andtrough

concentration(Cmin)ofEpiChronoliewithintheeffectivetherapeuticrangeofplasma

levelsfoundinpharmacokineticstudieswithEpilimEC.

5.3Preclinicalsafetydata

Therearenopreclinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedinother

sectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hypromellose

Ethylcellulose

Hydratedsilica

Filmcoat

Titaniumdioxide(E171)

Erythrosine(E127)

Indigocarmine(E132)

Blackironoxide(E172)

Hypromellose(E464)

Macrogol400

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 10

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

sanofi-aventisIrelandLtd

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA540/149/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:24thAugust2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/07/2010 CRN 2081454 page number: 11