EPILIM CHRONOSPHERE 750MG PROLONGED-RELEASE GRANUL

Main information

  • Trade name:
  • EPILIM CHRONOSPHERE 750MG PROLONGED-RELEASE GRANUL
  • Dosage:
  • 750 Milligram
  • Pharmaceutical form:
  • Granules Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPILIM CHRONOSPHERE 750MG PROLONGED-RELEASE GRANUL
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0540/150/008
  • Authorization date:
  • 02-03-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EpilimChronosphere750mgprolonged-releasegranules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachsachetofprolonged-releasegranulescontains:

Sodiumvalproate 500.06mg

Valproicacid 217.75mg

Equivalentto750mgsodiumvalproate.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasegranules.

Sachetscontainingsmall,off-whitetoslightlyyellow,waxymicrogranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inthetreatmentofgeneralised,partialorotherepilepsy.

Treatmentofmanicepisodeinbipolardisorderwhenlithiumiscontraindicatedornottolerated.Thecontinuationof

treatmentaftermanicepisodecouldbeconsideredinpatientswhohaverespondedtoEpilimChronosphereforacute

mania.

4.2Posologyandmethodofadministration

EpilimChronosphereisapharmaceuticalformparticularlysuitableforchildren(whentheyareabletoswallowsoft

food)andadultswithswallowingdifficulties.

EpilimChronosphereisacontrolledreleaseformulationofEpilim,whichreducespeakconcentrationandensuresmore

regularplasmaconcentrationthroughouttheday.

EpilimChronospheremaybegivenonceortwicedaily.

Inpatientswhereadequatecontrolhasbeenachieved,EpilimChronosphereformulationsareinterchangeablewith

otherconventionalorprolonged-releaseformulationsofEpilimonanequivalentdailydosagebasis.

Dailydosageshouldbeestablishedaccordingtoageandbodyweightandshouldbegiventothenearestwhole50mg

sachet.Partialsachetsshouldnotbeused.However,thewideindividualsensitivitytovalproateshouldalsobe

considered.

Agoodcorrelationhasnotbeenestablishedbetweendailydose,serumconcentrationandtherapeuticeffect,and

optimumdosageshouldbedeterminedprimarilyaccordingtotheclinicalresponse.Thedeterminationofvalproicacid

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whenadverseeffectsaresuspected.Thereportedeffectiverangeisusuallybetween40-100mg/L(300-700µmol/L).

InitiationofEpilimChronospheretherapy(oraladministration)

Inpatientswhoarenotcurrentlyusingotherantiepilepticdrugs,thedosageshouldpreferablybeincreasedby

successivedoselevelsat2-3dayintervalsinordertoreachtheoptimumdosageinaboutoneweek.

Inpatientswhoarealreadyreceivingantiepilepticagents,substitutionwithEpilimChronosphereshouldbe

progressive,theoptimumdosagebeingreachedinabout2weeksandothertreatmentsbeingtaperedoffandthen

stopped.

Otherantiepilepticagentshouldbeaddedprogressivelywherenecessary(see4.5."Druginteractions").

OraladministrationofEpilimChronosphere:practicalconsiderations

DosageinEpilepsy

Initialdailydosageisusually10-15mg/kg,thendosesaretitrateduptotheoptimumdosage(see4.2"Initiationof

EpilimChronospheretherapy").

Thisisgenerallywithintherange20-30mg/kg.Nevertheless,whereseizurecontrolisnotachievedwithinthisrange,

thedosemaybefurtherincreasedasrequired;patientsshouldbecarefullymonitoredwhenreceivingdailydoseshigher

than50mg/kg(see4.4"Precautions")

Inchildren,theusualdosageisabout30mg/kgperday.

Inadults,theusualdosageiswithintherange20-30mg/kgperday.

Inelderly,althoughthepharmacokineticsofEpilimChronospherearemodified,theyhavelimitedclinicalsignificance

anddosageshouldbedeterminedbyseizurecontrol.

ManicEpisodesinbipolardisorder:

Inadults:

Thedailydosageshouldbeestablishedandcontrolledindividuallybythetreatingphysician.

Theinitialrecommendeddailydoseis750mg.Inaddition,inclinicaltrialsastartingdoseof20mgvalproate/kgbody

weighthasalsoshownanacceptablesafetyprofile.Prolonged-releaseformulationscanbegivenonceortwicedaily.

Thedoseshouldbeincreasedasrapidlyaspossibletoachievethelowesttherapeuticdosewhichproducesthedesired

clinicaleffect.Thedailydoseshouldbeadaptedtotheclinicalresponsetoestablishthelowesteffectivedoseforthe

individualpatient.

Themeandailydoseusuallyrangesbetween1000and2000mgvalproate.Patientsreceivingdailydoseshigherthan

45mg/kg/daybodyweightshouldbecarefullymonitored.

Continuationoftreatmentofmanicepisodesinbipolardisordershouldbeadaptedindividuallyusingthelowest

effectivedose.

Inchildrenandadolescents:

ThesafetyandefficacyofEpilimChronosphereforthetreatmentofmanicepisodesinbipolardisorderhavenotbeen

evaluatedinpatientsagedlessthan18years.

Administration

EpilimChronosphereprolonged-releasegranulesshouldbesprinkledonasmallamountofsoftfoodorindrinks,

whichshouldbecoldoratroomtemperature,forexampleyoghurt,mousse,jam,icecream,milkshake,orangejuice

orsomethingsimilar.

Ifthegranulesaretakeninadrink,afterthedrinkhasbeenfinishedtheglassshouldberinsedwithasmallamountof

waterandthiswatershouldbetakenaswell,assomegranulesmaysticktotheglass.

Themixtureoffoodordrinkandgranulesshouldbeswallowedimmediately;thegranulesshouldnotbecrushedor

chewed.

Amixtureofthegranuleswithliquidorsoftfoodshouldnotbestoredforfutureuse.

EpilimChronosphereprolonged-releasegranulesshouldnotbesprinkledonwarmorhotfoodsanddrinks,for

examplesoup,coffee,tea,orsomethingsimilar.

Ifpreferredthegranulescanbepoureddirectlyintothemouthandwasheddownwithacolddrink.

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Thechronospheregranulescontainanon-absorbablematrixwhichisdesignedtoslowlyreleasetheactivesubstance.

Occasionallythematrixmaypassthroughthegastrointestinaltractwithoutdisintegratingandmaybevisibleinthe

patient’sstoolsbutthisdoesnotindicatethatthedrughasareducedeffect.

4.3Contraindications

-Activeliverdisease

-Personalorfamilyhistoryofseverehepaticdysfunction,especiallydrugrelated

-Hypersensitivitytosodiumvalproateortoanyoftheexcipients

-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,theincidenceofoccurrenceissignificantlyreducedandprogressivelydecreaseswithage.

Inmostcases,suchliverdamageoccurredduringthefirst6monthsoftherapy,theperiodofmaximumriskbeing2-12

weeks.

Suggestivesigns:

Clinicalsymptomsareessentialforearlydiagnosis.Inparticular,thefollowingconditions,whichmayprecede

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

-non-specificsymptoms,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

cessationofEpilimtherapy.

Asamatterofprecautionandincasetheyaretakenconcomitantlysalicylatesshouldalsobediscontinuedsincethey

employthesamemetabolicpathway.

Pancreatitis:Severepancreatitis,whichmayresultinfatalities,hasbeenveryrarelyreported.Patientsexperiencing

acuteabdominalpainshouldhaveapromptmedicalevaluation.Youngchildrenareatparticularrisk;thisrisk

decreaseswithincreasingage.Severeseizuresandsevereneurologicalimpairmentwithcombinationanticonvulsant

therapymayberiskfactors.Hepaticfailurewithpancreatitisincreasestheriskoffataloutcome.Incaseofpancreatitis,

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Womenofchildbearingpotential(seesection4.6):

AdecisiontouseEpiliminwomenofchildbearingpotentialshouldonlybetakenafterverycarefulevaluation,ifthe

benefitsofitsuseoutweightherisksofcongenitalanomaliestotheunbornchild.Thisdecisionistobetaken;before

Epilimisprescribedforthefirsttimeaswellasbeforeawomanalreadytreatedwithvalproicacidisplanninga

pregnancy.

Suicidalideationandbehaviour

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithantiepilepticagentsinseveralindications.A

meta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforvalproate.Thereforepatientsshouldbemonitoredforsignsofsuicidalideationand

behavioursandappropriatetreatmentshouldbeconsidered.Patients(andcaregiversofpatients)shouldbeadvisedto

seekmedicaladviceshouldsignsofsuicidalideationorbehaviouremerge.

4.4.2Precautions

Liverfunctiontestsshouldbecarriedoutbeforetherapy(seesection4.3"Contraindications"),andperiodicallyduring

thefirst6months,especiallyinpatientsatrisk(seesection4.4.1"Specialwarnings").

Aswithmostantiepilepticdrugs,increasedliverenzymesarecommon,particularlyatthebeginningoftherapy;they

arealsotransient.

Moreextensivebiologicalinvestigations(includingprothrombinrate)arerecommendedinthesepatients;areduction

indosagemaybeconsideredwhenappropriateandtestsshouldberepeatedasnecessary.

Children:Monotherapyisrecommendedinchildrenundertheageof3yearswhenprescribingEpilim,butthe

potentialbenefitofEpilimshouldbeweighedagainsttheriskofliverdamageorpancreatitisinsuchpatientspriorto

initiationoftherapy(seesection4.4.1"Specialwarnings").

Theconcomitantuseofsalicylatesshouldbeavoidedinchildrenunder3duetotheriskoflivertoxicity.

Haematological:Bloodtests(bloodcellcount,includingplateletcount,bleedingtimeandcoagulationtests)are

recommendedpriortoinitiationoftherapyorbeforesurgery,andincaseofspontaneousbruisingorbleeding(see

section4.8"UndesirableEffects").

Renalinsufficiency:Inpatientswithrenalinsufficiency,itmaybenecessarytodecreasedosage.Asmonitoringof

plasmaconcentrationsmaybemisleading,dosageshouldbeadjustedaccordingtoclinicalmonitoring(seesections4.2

"PosologyandMethodofAdministration"and5.2."PharmacokineticProperties").

Systemiclupuserythematosus:AlthoughimmunedisorderhaveonlyrarelybeennotedduringtheuseofEpilim,the

potentialbenefitofEpilimshouldbeweighedagainstitsriskinpatientswithsystemiclupuserythematosus(seealso

section4.8"UndesirableEffects").

Hyperammonaemia:Whenaureacycleenzymaticdeficiencyissuspected,metabolicinvestigationsshouldbe

performedpriortotreatmentbecauseoftheriskofhyperammonaemiawithEpilim.

Diabeticpatients:Epilimiseliminatedmainlythroughthekidneys,partlyintheformofketonebodies;thismaygive

falsepositivesintheurinetestingofpossiblediabetics.

Patientsshouldbewarnedoftheriskofweightgainattheinitiationoftherapy,andappropriatestrategiesshouldbe

adoptedtominimiseit(see4.8"UndesirableEffects").

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

4.5.1EffectsofEpilimonOtherDrugs

-Antipsychotics,MAOinhibitors,antidepressantsandbenzodiazepines

Epilimmaypotentiatetheeffectofotherpsychotropicssuchasantipsychotics,MAOinhibitors,antidepressantsand

benzodiazepines;therefore,clinicalmonitoringisadvisedandthedosageoftheotherpsychotropicsshouldbeadjusted

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Inparticular,aclinicalstudyhassuggestedthataddingolanzapinetovalproatetherapymaysignificantlyincreasethe

riskofcertainadverseeventsassociatedwitholanzapine.

-Phenobarbital

Epilimincreasesphenobarbitalplasmaconcentrations(duetoinhibitionofhepaticcatabolism)andsedationmayoccur,

particularlyinchildren.Therefore,clinicalmonitoringisrecommendedthroughoutthefirst15daysofcombined

treatmentwithimmediatereductionofphenobarbitaldosesifsedationoccursanddeterminationofphenobarbital

plasmalevelswhenappropriate.

-Primidone

Epilimincreasesprimidoneplasmalevelswithexacerbationofitsadverseeffects(suchassedation);thesesignscease

withlong-termtreatment.Clinicalmonitoringisrecommendedespeciallyatthebeginningofcombinedtherapywith

dosageadjustmentwhenappropriate.

-Phenytoin

Epilimdecreasesphenytointotalplasmaconcentration.MoreoverEpilimincreasesphenytoinfreeformwithpossible

overdosagesymptoms(valproicaciddisplacesphenytoinfromitsplasmaproteinbindingsitesandreducesitshepatic

catabolism).Thereforeclinicalmonitoringisrecommended;whenphenytoinplasmalevelsaredetermined,thefree

formshouldbeevaluated.

-Carbamazepine

ClinicaltoxicityhasbeenreportedwhenEpilimwasadministeredwithcarbamazepineasEpilimmaypotentiatetoxic

effectsofcarbamazepine.Clinicalmonitoringisrecommendedespeciallyatthebeginningofcombinedtherapywith

dosageadjustmentwhenappropriate.

-Lamotrigine

Theriskofrashmaybeincreasedbyco-administrationoflamotriginewithvalproicacid,whenlamotrigineisaddedontovalproic

acid.Epilimmayreducelamotriginemetabolismandincreaseitsmeanhalf-life,dosagesshouldbeadjusted(lamotriginedosage

decreased)whenappropriate.

-Zidovudine

Epilimmayraisezidovudineplasmaconcentrationleadingtoincreasedzidovudinetoxicity.

-VitaminK-dependentanticoagulants

Theanticoagulanteffectofwarfarinandothercoumarinanticoagulantsmaybeincreasedfollowingdisplacementfrom

plasmaproteinbindingsitesbyvalproicacid.Theprothrombintimeshouldbecloselymonitored.

4.5.2EffectsofOtherDrugsonEpilim

Antiepilepticswithenzymeinducingeffect(includingphenytoin,phenobarbital,carbamazepine)decreasevalproic

acidplasmaconcentrations.Dosagesshouldbeadjustedaccordingtoclinicalresponseandbloodlevelsincaseof

combinedtherapy.

Ontheotherhand,combinationoffelbamateandEpilimmayincreasevalproicacidplasmaconcentration.Epilim

dosageshouldbemonitored.

Mefloquineandchloroquineincreasevalproicacidmetabolismandhaveaconvulsingeffect.Theymaylowerthe

seizurethreshold;thereforeepilepticseizuresmayoccurincasesofcombinedtherapy.ThedosageofEpilimmayneed

tobeadjustedaccordingly.

IncaseofconcomitantuseofEpilimandhighlyproteinboundagents(e.g.aspirin),freevalproicacidplasmalevels

maybeincreased.

Valproicacidplasmalevelsmaybeincreased(asaresultofreducedhepaticmetabolism)incaseofconcomitantuse

withcimetidineorerythromycin.

Decreasesinbloodlevelsofvalproicacidhavebeenreportedwhenitisco-administeredwithcarbapenemagents

resultingina60-100%decreaseinvalproicacidlevelsinabouttwodays.Duetotherapidonsetandtheextentofthe

decrease,co-administrationofcarbapenemagentsinpatientsstabilisedonvalproicacidisnotconsideredtobe

manageableandthereforeshouldbeavoided(seesection4.4).

ColestyraminemaydecreasetheabsorptionofEpilim.

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dosageadjustmentmaybenecessarywhenitisco-administeredwithrifampicin.

4.5.3 OtherInteractions

CautionisadvisedwhenusingEpilimincombinationwithneweranti-epilepticswhosepharmacodynamicsmaynotbe

wellestablished.

Concomitantadministrationofvalproateandtopiramatehasbeenassociatedwithencephalopathyand/or

hyperammonemia.Patientstreatedwiththosetwodrugsshouldbecarefullymonitoredforsignsandsymptomsof

hyperammonemicencephalopathy.

Epilimusuallyhasnoenzyme-inducingeffect;asaconsequence,Epilimdoesnotreducetheefficacyof

oestroprogestativeagentsinwomenreceivinghormonalcontraception,includingtheoralcontraceptivepill.

ConcomitantfoodintakedoesnotsignificantlyinfluencethebioavailabilityofEpilimwhenadministeredasthe

Chronosphereformulation.

4.6Fertility,pregnancyandlactation

Thismedicineshouldnotbeusedduringpregnancyandinwomenofchild-bearingpotentialunlessclearlynecessary

(i.e.insituationswhereothertreatmentsareineffectiveornottolerated).Womenofchild-bearingpotentialhavetouse

effectivecontraceptionduringtreatment.

4.6.1 Pregnancy

Fromexperienceintreatingmotherswithepilepsy,theriskassociatedwiththeuseofEpilimduringpregnancyhas

beendescribedasfollows:

-Riskassociatedwithseizures

Duringpregnancy,maternaltonicclonicseizuresandstatusepilepticuswithhypoxiacarryaparticularriskofdeathfor

motherandfortheunbornchild.

-RiskassociatedwithEpilim

Inanimals:teratogeniceffectshavebeendemonstratedinthemouse,ratandrabbit.

Thereisanimalexperimentalevidencethathighplasmapeaklevelsandthesizeofanindividualdoseareassociated

withneuraltubedefects.

Inhumans:Availabledatasuggestanincreasedincidenceofminorormajormalformationsincluding,inparticular,

neuraltubedefects,craniofacialdefects,malformationofthelimbs,cardiovascularmalformationsandmultiple

anomaliesinvolvingvariousbodysystemsinoffspringborntomotherswithepilepsytreatedwithvalproatewhen

comparedtotheincidenceforcertainotherantiepilepticdrugs.Epilimuseisassociatedwithneuraltubedefectssuchas

myelomeningoceleandspinabifida.Thefrequencyofthiseffectisestimatedtobe1to2%.

DatasuggestthatantiepilepticpolytherapyincludingEpiliminducesahigherteratogenicriskthanmonotherapywith

valproateonly.

Datasuggestanassociationbetweenin-uteroEpilimexposureandariskofdevelopmentaldelayparticularlyofverbal

IQ,inchildrenborntomotherssufferingfromepilepsyandtreatedwithvalproate.Developmentaldelayisfrequently

associatedwithmalformationsand/ordysmorphicfeatures.However,itisdifficulttoestablishcausalrelationshipin

viewofpossibleconfoundingfactorssuchaslowmaternalorpaternalIQ,genetic,socialandenvironmentalfactors,

andpoormaternalseizurecontrolduringpregnancy.

Autismspectrumdisordershavealsobeenreportedinchildrenexposedtovalproateinutero.

-Inviewoftheabovedata

WomenofchildbearingpotentialshouldbeinformedindetailoftherisksandbenefitsoftheuseofEpilimduring

pregnancy.Specialistadviceisrequiredandphysiciansarestronglyencouragedtodiscussreproductiveissueswith

theirpatientsbeforeEpilimisprescribedforthefirsttimeorawomanalreadytreatedwithEpilimisplanninga

pregnancy.

Ifawomanplanspregnancy,Epilimtherapyshouldbereassessedwhatevertheindication.Inbipolardisorders

indication,cessationofEpilimprophylaxisshouldbeconsidered.If,inanyindication,furthertoacarefulevaluationof

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dosesoverthedayatthelowesteffectivedose.Theuseofaprolongedreleaseformulationmaybepreferabletoany

othertreatmentform.

Inadditionifappropriate,folatesupplementationshouldbestartedbeforepregnancyandatrelevantdosage(5mg

daily)asitmayminimizetheriskofneuraltubedefects.

Duringpregnancy,valproatetherapyshouldnotbediscontinuedwithoutreassessmentofthebenefit/risk.

Specializedprenatalmonitoringshouldbeinstitutedinordertodetectthepossibleoccurrenceofneuraltubedefector

othermalformations.Pregnanciesshouldbecarefullyscreenedbyultrasound,andothertechniquesifappropriate(see

Section4.4SpecialWarningsandSpecialPrecautionsforUse).

-Riskintheneonate

Veryrarecasesofhaemorrhagicsyndromehavebeenreportedinneonateswhosemothershavetakenvalproateduring

pregnancy.Thishaemorrhagicsyndromeisrelatedtohypofibrinogenemia;afibrinogenemiahasalsobeenreportedand

maybefatal.Thesearepossiblyassociatedwithadecreaseofcoagulationfactors.However,thissyndromehastobe

distinguishedfromthedecreaseofthevitamin-Kfactorsinducedbyphenobarbitalandotheranti-epilepticenzyme

inducingdrugs.

Therefore,plateletcount,fibrinogenplasmalevel,coagulationtestsandcoagulationfactorsshouldbeinvestigatedin

neonates.

4.6.2 Lactation

ExcretionofEpiliminbreastmilkislow,withaconcentrationbetween1%to10%oftotalmaternalserumlevels.

Basedonliteratureandclinicalexperience,breastfeedingcanbeenvisaged,takingintoaccounttheEpilimsafety

profile,especiallyhaematologicaldisorders(seesection4.8UndesirableEffects).

4.7Effectsonabilitytodriveandusemachines

UseofEpilimmayprovideseizurecontrolsuchthatthepatientmaybeeligibletoholdadrivinglicence.

Patientsshouldbewarnedoftheriskoftransientdrowsinessespeciallyincasesofanticonvulsantpolytherapyor

associationwithbenzodiazepines(seesection4.5InteractionswithOtherMedicamentsandOtherFormsofInteraction).

4.8Undesirableeffects

Congenital,familialandgeneticdisorders:(seesection4.6“PregnancyandLactation”).

Hepatobiliarydisorders:rarecasesofliverinjury(seesection4.4.1“Specialwarnings”).

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

usuallydisappearafterafewdayswithoutdiscontinuingtreatment.Theseproblemscanusuallybeovercomebytaking

EpilimwithorafterfoodorbyusingEntericCoatedEpilim.

Veryrarecasesofpancreatitis,sometimeslethal,havebeenreported(seesection4.4“SpecialWarningsandSpecial

PrecautionsforUse”).

Nervoussystemdisorders:Sedationhasbeenreportedoccasionally,usuallywhenincombinationwithother

anticonvulsants.Inmonotherapyitoccurredearlyintreatmentonrareoccasionsandisusuallytransient.Rarecasesof

lethargyandconfusion,occasionallyprogressingtostupor,sometimeswithassociatedhallucinationsorconvulsions

havebeenreported.Encephalopathyandcomahaveveryrarelybeenobserved.Thesecaseshaveoftenbeenassociated

withtoohighastartingdoseortoorapidadoseescalationorconcomitantuseofotheranticonvulsants,notably

phenobarbitalortopiramate.Theyhaveusuallybeenreversibleonwithdrawaloftreatmentorreductionofdosage.

Extrapyramidaldisorders.

Veryrarecasesofreversibleparkinsonism,orreversibledementiaassociatedwithreversiblecerebralatrophyhave

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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,includingpureredcellaplasia.Agranulocytosis.Isolatedfindingsofareductioninblood

fibrinogenand/orincreaseinprothrombintimehavebeenreported,usuallywithoutassociatedclinicalsignsand

particularlywithhighdoses(Epilimhasaninhibitoryeffectonthesecondphaseofplateletaggregation).Spontaneous

bruisingorbleedingisanindicationforwithdrawalofmedicationpendinginvestigations(seealsosection4.6

“PregnancyandLactation”).

Skinandsubcutaneoustissuedisorders:

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

Transientand/ordoserelatedalopecia,hasoftenbeenreported.Regrowthnormallybeginswithinsixmonths,although

thehairmaygrowbackcurlierthanbefore.

Reproductivesystemandbreastdisorders:

Amenorrhoeaanddysmenorrheahavebeenreported.Veryrarelygynaecomastiahasoccurred.

Vasculardisorders:

Theoccurrenceofvasculitishasoccasionallybeenreported.

Earandlabyrinthdisorders:

Deafness,eitherreversibleorirreversiblehasbeenreportedrarely.

Renalandurinarydisorders:

TherehavebeenisolatedreportsofareversibleFanconi’ssyndrome(adefectinproximalrenaltubularfunctiongiving

risetoglycosuria,aminoaciduria,phosphaturia,anduricosuria)butthemodeofactionisasyetunclear.Veryrare

casesofenuresishavebeenreported.

Immunesystemdisorders:

Angioedema,DrugRashwithEosinophiliaandSystemicSymptoms(DRESS)syndrome.Allergicreactions(ranging

fromrashtohypersensitivityreactions)havebeenreported.

Psychiatricdisorders:

Confusion

Generaldisordersandadministrationsiteconditions:

Veryrarecasesofnon-severeperipheraloedemahavebeenreported.

Increaseinweightmayalsooccur.Sinceitisariskfactorforpolycysticovarysyndrome,itshouldbecarefully

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4.9Overdose

CasesofaccidentalanddeliberateEpilimoverdosagehavebeenreported.Atplasmaconcentrationsofupto5to6

timesthemaximumtherapeuticlevels,thereareunlikelytobeanysymptomsotherthannausea,vomitingand

dizziness.

Signsofmassiveoverdose,i.e.plasmaconcentration10to20timesmaximumtherapeuticlevels,usuallyincludeCNS

depressionorcomawithmuscularhypotonia,hyporeflexia,miosis,impairedrespiratoryfunction,metabolicacidosis.

Deathshaveoccurredfollowingmassiveoverdose;nevertheless,afavourableoutcomeisusual.

Symptomsmayhoweverbevariableandseizureshavebeenreportedinthepresenceofveryhighplasmalevels(see

alsosection5.2“PharmacokineticProperties”).Casesofintracranialhypertensionrelatedtocerebraloedemahavebeen

reported.

Hospitalmanagementofoverdoseshouldbesymptomatic:gastriclavage,cardio-respiratorymonitoring.

Haemodialysisandhaemoperfusionhavebeenusedsuccessfully.Naloxonehasalsobeenusedinafewisolatedcases.

Incasesofmassiveoverdose,hemodialysisandhemoperfusionhavebeenusedsuccessfully.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Valproicacidandsodiumvalproateareanticonvulsants.

ThemostlikelymodeofactionforEpilimispotentiationoftheinhibitoryactionofgammaaminobutyricacid

(GABA)throughanactiononthefurthersynthesisorfurthermetabolismofGABA.

Incertaininvitrostudies,ithasbeenreportedthatEpilimcanstimulateHIV.Howeverthiseffectismodest,variable,

unrelatedtothedoseandnotdocumentedinman.

5.2Pharmacokineticproperties

Thehalf-lifeofsodiumvalproateisusuallyreportedtobewithintherangeof8-20hours.Itisusuallyshorterin

children.

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

Thisreportedrangemaydependontimeofsamplingandpresenceofco-medication.

Thepercentageoffree(unbound)drugisusuallybetween6%and15%oftotalplasmalevels.Anincreasedincidence

ofadverseeffectsmayoccurwithplasmalevelsabovetheeffectivetherapeuticrange.

Thepharmacological(ortherapeutic)effectsofEpilimChronospheremaynotbeclearlycorrelatedwiththetotalor

free(unbound)plasmavalproicacidlevels.

EpilimChronosphereisaprolonged(ormodified)releaseformulationofEpilimwhichreducespeakconcentrationand

ensuresmoreevenplasmaconcentrationsthroughoutthedaycomparedwithotherestablishedconventionaland

modifiedreleaseEpilimformulations.Followingtwicedailyadministrationofasamedose,therangeofplasma

fluctuationsisapproximatelyreducedbyhalf.

ComparedwithimmediatereleaseformsofEpilimitischaracterizedatanequivalentdoseby:

asimilarbioavailability,

alowerCmax(decreaseofapproximately25%),

arelativelystableplateaubetween4and14hoursafteradministration.

Steady-statepharmacokineticdataindicatethatthepeakconcentration(Cmax)andtroughconcentration

(Cmin)ofEpilimChronosphereliewithintheeffectivetherapeuticrangeofplasmalevelsfoundinpharmacokinetic

studieswithEpilimEC.

Incaseswheremeasurementofplasmalevelsisconsiderednecessary,thepharmacokineticsofEpilimChronosphere

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Thepeakplasmalevelisachievedapproximately7hoursafteradministration,withaneliminationhalf-lifebetween13

and16hours.

Thispharmacokineticprofileisnotaffectedbytakingthedrugwithfood.

5.3Preclinicalsafetydata

Therearenopreclinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedinother

sectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hardparaffin,glyceroldibehenate,colloidalhydratedsilica.

6.2Incompatibilities

Thismedicinalproductmustnotbeadministeredwithhotmealsordrinks.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

EpilimChronosphere750mgprolonged-releasegranulesarefilledintosachetsof:

3layerscomplex:printedpaper,aluminium,ionomerresincomplex,

3layerscomplex:printedpaperwithnitrocellulosicglaze,aluminium,ionomerresincomplex.

Eachsachetcontainstheequivalentof750mgsodiumvalproate.

EpilimChronospheresachetsareavailableinpacksizesof30and50sachets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

Sanofi-aventisIrelandLimited

CitywestBusinessCampus

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8MARKETINGAUTHORISATIONNUMBER

PA540/150/8

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:2ndMarch2007

10DATEOFREVISIONOFTHETEXT

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