summary of product characteristics episenta® 500mg...

1

SUMMARY OF PRODUCT CHARACTERISTICSEpisenta® 500mg Prolonged-release Granules

1 NAME OF THE MEDICINAL PRODUCTEpisenta® 500mg Prolonged-release Granules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach sachet of prolonged-release granules contains sodium valproate 500mg.

For excipients see 6.1.

3 PHARMACEUTICAL FORMProlonged-release granules.

White or almost white, round, film-coated prolonged-release granules.

4 CLINICAL PARTICULARS

4.1 Therapeutic indicationsSodium valproate is used in the:

• treatmentofallformsofepilepsy

• treatmentofmanicepisodeinbipolardisorderwhenlithiumiscontraindicatedornottolerated. Thecontinuationoftreatmentaftermanicepisodecouldbeconsideredinpatientswhohaveresponded to sodium valproate for acute mania

4.2 Posology and method of administrationTreatmentinallformsofepilepsy:

Dosagerequirementsvaryaccordingtoageandbodyweightandshouldbeadjustedindividuallytoachieveadequateseizurecontrol.Thedailydosageshouldbegivenin1–2singledoses.

Monotherapy: usual requirements are as follows:

Adults: Dosageshouldstartat600mgdailyincreasingby150-300mgatthreedayintervalsuntilcontrolisachieved.Thisisgenerallywithinthedosagerangeof1000mgto2000mgperdayi.e.20-30mg/kgbodyweightdaily.Whereadequatecontrolisnotachievedwithinthisrangethedosemaybefurtherincreasedtoamaximumof2500mgperday.

Children over 20kg:Initialdosageshouldbe300mg/dayincreasinguntilcontrolisachieved.Thisisusuallywithintherange20-30mg/kgbodyweightperday.Whereadequatecontrolisnotachievedwithinthisrange,thedosemaybeincreasedto35mg/kgbodyweightperday.

100369 DESITIN Episenta 500mg SmPC AW.indd 1 02/08/2012 14:51

2

Children under 20kg:20mg/kgbodyweightperday;inseverecasesthismaybeincreasedupto 40mg/kg/day.

Use in the elderly:Careshouldbetakenwhenadjustingdosageintheelderlysincethepharmacokineticsofsodiumvalproatearemodified.Thevolumeofdistributionisincreasedintheelderlyandbecauseofdecreasedbindingtoserumalbumin,theproportionoffreedrugisincreased.Thiswillaffecttheclinicalinterpretationofplasmavalproicacidlevels.Dosageshouldbedeterminedbyseizurecontrol.

In patients with renal insufficiency:Itmaybenecessarytodecreasedosage.Dosageshouldbeadjustedaccordingtoclinicalmonitoringsincemonitoringofplasmaconcentrationsmaybemisleading.

In patients with hepatic insufficiency:Salicylatesshouldnotbeusedconcomitantlywithsodiumvalproatesincetheyemploythesamemetabolicpathway(seesection4.4Specialwarningsandprecautionsforuseand4.8Undesirableeffects).

Liverdysfunction,includinghepaticfailureresultinginfatalities,hasoccurredinpatientswhosetreatmentincludedvalproicacid(seesection4.3Contraindicationsand4.4Specialwarningsandprecautionsforuse).

Salicylatesshouldnotbeusedinchildrenunder16years(seeaspirin/salicylateproductinformationonReye’ssyndrome).Inadditioninconjunctionwithsodiumvalproate,concomitantuseinchildrenunder3yearscanincreasetheriskoflivertoxicity(seesection4.4Specialwarnings).

Combined Therapy: WhenstartingEpisenta®inpatientsalreadyonanticonvulsants,theseshouldbetaperedslowly;initiationofEpisenta®treatmentshouldthenbegradual,withtargetdosebeingreachedafterabout2weeks.Incertaincasesitmaybenecessarytoraisethedoseby5to10mg/kg/daywhenusedincombinationwithliverenzymeinducingdrugssuchasphenytoin,phenobarbitalandcarbamazepine.Onceknownenzymeinducershavebeenwithdrawnitmaybepossibletomaintainseizure control on a reduced dose of Episenta®.

Whenbarbituratesarebeingadministeredconcomitantlyandparticularlyifsedationisobserved(particularlyinchildren)thedosageofbarbiturateshouldbereduced.

N.B.Inchildrenrequiringdoseshigherthan40mg/kg/dayclinicalchemistryandhaematologicalparametersshouldbemonitored.

Optimumdosageismainlydeterminedbyseizurecontrolandroutinemeasurementofplasmalevelsisunnecessary.However,amethodformeasurementofplasmalevelsisavailableandmaybehelpfulwherethereispoorcontrolorsideeffectsaresuspected(seesection5.2Pharmacokineticproperties).

Manic episodes in bipolar disorder:In adults: Thedailydosageshouldbeestablishedandcontrolledindividuallybythetreatingphysician.Theinitialrecommendeddailydoseis750mg.Inaddition,inclinicaltrialsastartingdoseof20mgsodiumvalproate/kgbodyweighthasalsoshownanacceptablesafetyprofile.Prolonged-releaseformulationscanbegivenonceortwicedaily.Thedoseshouldbeincreasedasrapidlyaspossibletoachievethelowesttherapeuticdosewhichproducesthedesiredclinicaleffect.Thedailydoseshouldbeadaptedtotheclinicalresponsetoestablishthelowesteffectivedosefortheindividualpatient.Themeandailydoseusuallyrangesbetween1000and2000mgsodiumvalproate.Patientsreceivingdailydoseshigherthan45mg/kg/daybodyweightshouldbecarefullymonitored.Continuationoftreatmentofmanicepisodesinbipolardisordershouldbeadaptedindividuallyusingthelowesteffectivedose.

In children and adolescents: ThesafetyandefficacyofEpisenta®forthetreatmentofmanicepisodesinbipolardisorderhavenotbeenevaluatedinpatientsagedlessthan18years.

100369 DESITIN Episenta 500mg SmPC AW.indd 2 02/08/2012 14:51

3

Method of administration

For oral administration.Thecontentsofthesachetmaybesprinkledorstirredintosoftfoodordrinksandswallowedimmediatelywithoutchewing,orcrushingtheprolonged-releasegranules.Thefoodordrinkshouldbecoldoratroomtemperature.Amixtureofthegranuleswithliquidorsoftfoodshouldnotbestoredforfutureuse.Ifthecontentsofthesachetaretakeninadrink,assomegranulesmaysticktotheglassafterthedrinkhasbeenfinished,theglassshouldberinsedwithasmallamountofwaterandthiswaterswallowedaswell.Theprolonged-releasegranulesshouldnotbegiveninbabies’bottlesastheycanblocktheteat.

WhenchangingfromsodiumvalproateentericcoatedtabletstoEpisenta®itisrecommendedtokeepthesamedailydose.

4.3 ContraindicationsActiveliverdisease.

Personalorfamilyhistoryofseverehepaticdysfunction,especiallydrugrelated.

Porphyria.

Hypersensitivitytovalproateoranyoftheexcipients.

4.4 Special warnings and precautions for useSuicidalideationandbehaviourhavebeenreportedinpatientstreatedwithantiepilepticagentsinseveralindications.Ameta-analysisofrandomisedplacebocontrolledtrialsofantiepilepticdrugshasalsoshownasmallincreasedriskofsuicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethepossibilityofanincreasedriskforsodiumvalproate.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshouldbeconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidalideationorbehaviouremerge.

Althoughthereisnospecificevidenceofsuddenrecurrenceofunderlyingsymptomsfollowingwithdrawalofvalproate,discontinuationshouldnormallyonlybedoneunderthesupervisionofaspecialistinagradualmanner.Thisisduetothepossibilityofsuddenalterationsinplasmaconcentrationsgivingrisetoarecurrenceofsymptoms.

Theconcomitantuseofsodiumvalproateandcarbapenemisnotrecommended(seesection4.5Interactionwithothermedicinalproductsandotherformsofinteraction).

100369 DESITIN Episenta 500mg SmPC AW.indd 3 02/08/2012 14:51

4

Hepaticdysfunction:

Conditions of occurrence:Severeliverdamage,includinghepaticfailuresometimesresultinginfatalities,hasbeenveryrarelyreported.Experienceinepilepsyhasindicatedthatpatientsmostatrisk,especiallyincasesofmultipleanticonvulsantstherapy,areinfantsandinparticularyoungchildrenundertheageof3andthosewithsevereseizuredisorders,organicbraindisease,and(or)congenitalmetabolicordegenerativediseaseassociatedwithmentalretardation.Aftertheageof3,theincidenceofoccurrenceissignificantlyreducedandprogressivelydecreaseswithage.Theconcomitantuseofsalicylatesshouldbeavoidedinchildrenunder3duetotheriskoflivertoxicity.Additionally,salicylatesshouldnotbeusedinchildrenunder16yearsofage(seeaspirin/salicylateproductinformationonReye’ssyndrome).

Monotherapyisrecommendedinchildrenundertheageof3yearswhenprescribingEpisenta®,butthepotentialbenefitofEpisenta®shouldbeweighedagainsttheriskofliverdamageorpancreatitisinsuchpatientspriortoinitiationoftherapy.

Inmostcases,suchliverdamageoccurredduringthefirst6monthsoftherapy,theperiodofmaximumriskbeing2–12weeks.

Suggestive signs:Clinicalsymptomsareessentialforearlydiagnosis.Inparticularthefollowingconditions,whichmayprecedejaundice,shouldbetakenintoconsideration,especiallyinpatientsatrisk(seeabove:Conditionsofoccurrence):

• non-specificsymptoms,usuallyofsuddenonset,suchasasthenia,malaise,anorexia,lethargy,oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain

• inpatientswithepilepsy,recurrenceofseizures

These are an indication for immediate withdrawal of the drug.

Patients(ortheircarers),shouldbeinstructedtoreportimmediatelyanysuchsignstoaphysicianshouldtheyoccur.Investigationsincludingclinicalexaminationandbiologicalassessmentofliverfunctionshouldbeundertakenimmediately.

Detection:Liverfunctionshouldbemeasuredbeforeandthenperiodicallymonitoredduringthefirst6monthsoftherapy,especiallyinthosewhoseematrisk,andthosewithapriorhistoryofliverdisease.Amongstusualinvestigations,testswhichreflectproteinsynthesis,particularlyprothrombinrate,aremostrelevant.Confirmationofanabnormallylowprothrombinrate,particularlyinassociationwithotherbiologicalabnormalities(significantdecreasesinfibrinogenandcoagulationfactors;increasedbilirubinlevelandraisedtransaminases)requirecessationofEpisenta®therapy.

Asamatterofprecautionandincasetheyaretakenconcomitantlysalicylatesshouldalsobediscontinuedsincetheyemploythesamemetabolicpathway.

Aswithmostantiepilepticdrugs,increasedliverenzymesarecommon,particularlyatthebeginningof therapy;theyarealsotransient.

Moreextensivebiologicalinvestigations(includingprothrombinrate)arerecommendedinthesepatients;areductionindosagemaybeconsideredwhenappropriateandtestsshouldberepeatedas necessary.

100369 DESITIN Episenta 500mg SmPC AW.indd 4 02/08/2012 14:51

5

Pancreatitis:Pancreatitis,whichmaybesevereandresultinfatalities,hasbeenveryrarelyreported.Patientsexperiencingnausea,vomitingoracuteabdominalpainshouldhaveapromptmedicalevaluation(includingmeasurementofserumamylase).Youngchildrenareatparticularrisk;thisriskdecreaseswithincreasingage.Severeseizuresandsevereneurologicalimpairmentwithcombinationanticonvulsanttherapymayberiskfactors.Hepaticfailurewithpancreatitisincreasestheriskoffataloutcome.Incaseofpancreatitis,Episenta®shouldbediscontinued.

Haematological:Bloodtests(bloodcellcount,includingplateletcount,bleedingtimeandcoagulationtests)arerecommendedpriortoinitiationoftherapyorbeforesurgery,andincaseofspontaneousbruisingorbleeding(seesection4.8Undesirableeffects).

Renal insufficiency:Inpatientswithrenalinsufficiency,itmaybenecessarytodecreasedosage.Asmonitoringofplasmaconcentrationsmaybemisleading,dosageshouldbeadjustedaccordingtoclinicalmonitoring(seesections4.2Posologyandmethodofadministrationand5.2Pharmacokineticproperties).

Systemic lupus erythematosus:Althoughimmunedisordershaveonlyrarelybeennotedduringtheuseofsodiumvalproate,thepotentialbenefitofEpisenta®shouldbeweighedagainstitspotentialriskinpatientswithsystemiclupuserythematosus(seesection4.8Undesirableeffects).

Hyperammonaemia:Whenureacycleenzymaticdeficiencyissuspected,metabolicinvestigationsshouldbeperformedpriortotreatmentbecauseofriskofhyperammonaemiawithsodiumvalproate.

Weight gain:Sodiumvalproateverycommonlycausesweightgain,whichmaybemarkedandprogressive.Patientsshouldbewarnedoftheriskofweightgainattheinitiationoftherapyandappropriatestrategiesshouldbeadoptedtominimiseit(seesection4.8Undesirableeffects).

Women of child-bearing potential (see section 4.6 Pregnancy and lactation):AdecisiontouseEpisenta® inwomenofchild-bearingpotentialshouldnotbetakenwithoutspecialistneurologicaladvice,andonlyifthebenefitsofitsuseoutweighthepotentialrisksofcongenitalanomaliestotheunbornchild.ThisdecisionistobetakenbeforeEpisenta®isprescribedforthefirsttimeaswellasbeforeawomanalreadytreatedwithvalproicacidisplanningpregnancy.Adequatecounsellingshouldbemadeavailabletoallwomenofchild-bearingpotentialregardingtherisksassociatedwithpregnancy(seesection4.6Pregnancyandlactation).

Diabetic Patients:Sodiumvalproateiseliminatedmainlythroughthekidneys,partlyintheformofketonebodies:thismaygivefalsepositiveintheurinetestingofpossiblediabetics.

Granules in Stools:Theprolonged-releasegranulesaresurroundedbyanindigestiblecelluloseshellthroughwhichthesodiumvalproateisreleasedandtheseshellswillbeseenaswhiteresiduesinthestoolsofthepatient.Therearenosafetyissuesconcerningsuchresidues.

100369 DESITIN Episenta 500mg SmPC AW.indd 5 02/08/2012 14:51

6

4.5 Interaction with other medicinal products and other forms of interaction

4.5.1 Effects of Episenta® on other drugsLikemanyotherdrugs,Episenta® maypotentiatetheeffectofotherpsychotropics,suchasantipsychotics,monoamineoxidaseinhibitors,antidepressantsandbenzodiazepines.Therefore,clinicalmonitoringandthedosageofotherpsychotropicsshouldbeadjustedwhenappropriate.Inparticular,aclinicalstudyhassuggestedthataddingolanzapinetovalproateorlithiumtherapymaysignificantlyincreasetheriskofcertainadverseeventsassociatedwitholanzapinee.g.neutropenia,tremor,drymouth, increased appetite and weight gain, speech disorder and somnolence.

Sodiumvalproateincreasesphenobarbitalplasmaconcentrationsandsedationmayoccur,particularlyinchildren.Clinicalmonitoringisrecommendedthroughoutthefirst15daysofcombinedtreatmentwithanimmediatereductionofphenobarbitaldosesifsedationoccursanddeterminationofphenobarbitallevelswhenappropriate.

Sodiumvalproateincreasesprimidoneplasmalevelscausinganexacerbationofsideeffects,e.g.sedation;thesesignsceasewithlongtermtreatment.Clinicalmonitoringisrecommendedespeciallywheninitiatingcombinedtherapywithdosageadjustmentasnecessary.

Phenytointotalplasmalevelsaredecreasedbysodiumvalproateacid;thefreeformofphenytoinisincreasedleadingtopossibleoverdosagesymptoms.Therefore,clinicalmonitoringisrecommendedwiththefreeformofphenytoinbeingmeasured.

Thetoxiceffectsofcarbamazepinemaybepotentiatedbysodiumvalproaterequiringclinicalmonitoringanddosageadjustmentparticularlyatinitiationofcombinedtherapy.

Sodiumvalproatemayreducelamotriginemetabolismandincreaseitsmeanhalf-life.Thedosage oflamotrigineshouldbedecreasedasnecessary.Theriskofrashisincreasedincombinedtherapy with lamotrigine.

Sodiumvalproatemayraisezidovudineplasmaconcentrationsleadingtoincreasedzidovudinetoxicity.

Theanticoagulanteffectofwarfarinandothercoumarinanticoagulantsmaybeincreasedfollowingdisplacementfromtheplasmaproteinbindingsitebyvalproate.Theprothrombintimeshouldbe closelymonitored.

Co-administrationoftemozolomideandsodiumvalproatemaycauseasmalldecreaseintheclearanceoftemozolomidethatisnotthoughttobeclinicallyrelevant.

4.5.2 Effects of other drugs on Episenta®Antiepilepticswithenzymeinducingeffectse.g.phenytoin,phenobarbital,carbamazepine,decreasevalproateplasmalevels.Plasmalevelsshouldbemonitoredanddosageadjustedaccordingly.Ontheotherhand,combinationoffelbamateandsodiumvalproatemayincreasevalproicacidplasmaconcentration.Episenta®dosageshouldbemonitored.

Mefloquineandchloroquineincreasesvalproatemetabolismandthereforeepilepticseizuresmayoccurincombinedtherapy.Thedosageofsodiumvalproatemayneedadjustment.

Freevalproatelevelsmaybeincreasedinthecaseofconcomitantusewithhighlyproteinboundagentse.g.acetylsalicylicacid.Valproateplasmalevelsmayalsobeincreasedwhenusedconcomitantlywithcimetidineorerythromycinasaresultofreducedhepaticmetabolism.

100369 DESITIN Episenta 500mg SmPC AW.indd 6 02/08/2012 14:51

7

Decreasesinbloodlevelsofvalproicacidhavebeenreportedwhenitiscoadministeredwithcarbapenemagentsresultingina60–100%decreaseinvalproicacidlevelsinabouttwodays. Duetorapidonsetandtheextentofthedecrease,coadministrationofcarbapenemagentsinpatientsstabilisedonvalproicacidisnotconsideredtobemanageableandthereforeshouldbeavoided(seesection4.4Specialwarningsandprecautionsforuse).

Colestyraminemaydecreasetheabsorptionofvalproate.

Rifampicinmaydecreasethevalproatebloodlevelsresultinginalackoftherapeuticeffect.Therefore,valproatedosageadjustmentmaybenecessarywhenitisco-administeredwithrifampicin.

4.5.3 Other interactionSodiumvalproateusuallyhasnoenzyme-inducingeffect;asaconsequence,Episenta®doesnotreduceefficacyofoestroprogestativeagentsinwomenreceivinghormonalcontraception,includingtheoralcontraceptive pill.

CautionisadvisedwhenusingEpisenta®incombinationwithnewerantiepilepticswhosepharmacodynamicsmaynotbewellestablished.

Concomitantadministrationofvalproateandtopiramatehasbeenassociatedwithencephalopathyand/orhyperammonaemia.Inpatientstakingthesetwodrugs,carefulmonitoringofsignsandsymptomsisadvisedinparticularlyat-riskpatientssuchasthosewithpre-existingencephalopathy.

4.6 Pregnancy and lactationWomenofchild-bearingpotentialshouldnotbestartedonEpisenta®withoutspecialist neurological advice.

Adequatecounsellingshouldbemadeavailabletoallwomenwithepilepsyofchild-bearingpotentialregardingtherisksassociatedwithpregnancybecauseofthepotentialteratogenicrisktothefoetus(seesection4.6.1Pregnancy).WomenwhoaretakingEpisenta®andwhomaybecomepregnantshouldreceivespecialistneurologicaladviceandthebenefitsofitsuseshouldbeweighedagainstthe risks.

Sodiumvalproateistheantiepilepticofchoiceinpatientswithcertaintypesofepilepsysuchasgeneralisedepilepsy±mycolonus/photosensitivity.Forpartialepilepsy,Episenta®shouldbeusedonlyin patients resistant to other treatment.

Ifpregnancyisplanned,considerationshouldbegiventocessationofEpisenta®treatment, if appropriate.

WhenEpisenta®treatmentisdeemednecessary,precautionstominimizethepotentialteratogenicrisksshouldbefollowed(seesection4.6.1paragraphentitled‘Inviewoftheabovedata’).

100369 DESITIN Episenta 500mg SmPC AW.indd 7 02/08/2012 14:51

8

4.6.1 PregnancyFromexperienceintreatingmotherswithepilepsy,theriskassociatedwiththeuseofvalproateduringpregnancyhasbeendescribedasfollows:

Risk associated with epilepsy and antiepileptics

Inoffspringborntomotherswithepilepsyreceivinganyantiepileptictreatment,theoverallrateofmalformationshasbeendemonstratedtobe2to3timeshigherthantherate(approximately3%)reportedinthegeneralpopulation.Althoughanincreasednumberofchildrenwithmalformationshavebeenreportedincasesofmultipledrugtherapy,therespectiveroleoftreatmentsanddiseaseincausingthemalformationshasnotbeenformallyestablished.Malformationsmostfrequentlyencounteredarecleft lip and cardiovascular malformations.

Epidemiologicalstudieshavesuggestedanassociationbetweenin-uteroexposuretosodiumvalproateandariskofdevelopmentaldelay.Developmentaldelayhasbeenreportedinchildrenborntomotherswithepilepsy.Itisnotpossibletodifferentiatewhatmaybeduetogenetic,social,environmentalfactors,maternalepilepsyorantiepileptictreatment.Manyfactorsincludingmaternalepilepsymayalsocontributetothisriskbutitisdifficultytoquantifytherelativecontributionsoftheseorofmaternalantiepileptictreatment.Notwithstandingthosepotentialrisks,nosuddendiscontinuationintheantiepileptictherapyshouldbeundertakenasthismayleadtobreakthroughseizureswhichcouldhaveseriousconsequencesforboththemotherandthefoetus.

Risk associated with seizures

Duringpregnancy,maternaltonicclonicseizuresandstatusepilepticuswithhypoxiacarryaparticularriskofdeathformotherandtheunbornchild.

Risks associated with valproate

Inanimals:teratogeniceffectshavebeendemonstratedinthemouse,ratandrabbit.Thereisanimalexperimentalevidencethathighplasmapeaklevelsandthesizeofanindividualdoseareassociatedwithneuraltubedefects.

Inhumans:valproateisassociatedwithneuraltubedefectssuchasmyelomeningoceleandspinabifida.Thefrequencyofthiseffectisestimatedtobe1to2%.Anincreasedincidenceofminorormajormalformationsincludingneuraltubedefects,craniofacialdefects,malformationofthelimbs,cardiovascularmalformations,hypospadiasandmultipleanomaliesinvolvingvariousbodysystemshasbeenreportedinoffspringborntomotherswithepilepsytreatedwithvalproate.Thedatasuggeststhattheuseofvalproateisassociatedwithagreaterriskofcertaintypesofthesemalformations (inparticularneuraltubedefects)thansomeotherantiepilepticdrugs.

Bothvalproatemonotherapyandvalproateaspartofpolytherapyareassociatedwithabnormalpregnancyoutcome.Availabledatasuggeststhatantiepilepticpolytherapyincludingsodiumvalproateisassociatedwithahigherriskofabnormalpregnancyoutcomethansodiumvalproatemonotherapy.

Datahavesuggestedanassociationbetweenin-uteroexposuretovalproateandtheriskofdevelopmentaldelay(frequentlyassociatedwithdysmorphicfeatures),particularlyofverbalIQ.However,theinterpretationoftheobservedfindingsinoffspringborntomotherswithepilepsytreatedwithsodiumvalproateremainsuncertain,intheviewofpossibleconfoundingfactorssuchaslowmaternalIQ,genetic,social,environmentalfactorsandpoormaternalseizurecontrolduringpregnancy.

Autismspectrumdisordershavealsobeenreportedinchildrenexposedtovalproateinutero.

100369 DESITIN Episenta 500mg SmPC AW.indd 8 02/08/2012 14:51

9

In view of the above data

Whenawomanisplanningpregnancy,thisprovidesanopportunitytoreviewtheneedforantiepileptictreatment.Womenofchild-bearingageshouldbeinformedoftherisksandbenefitsofcontinuingantiepileptictreatmentthroughoutpregnancy.SpecialistadviceisrequiredandphysiciansarestronglyencouragedtodiscussreproductiveissueswiththeirpatientsbeforeEpisenta®isprescribedforthefirsttimeorawomanalreadytreatedwithEpisenta®isplanningapregnancy.

Folate supplementation, priortopregnancy,hasbeendemonstratedtoreducetheincidenceofneuraltubedefectsintheoffspringofwomenathighrisk.Althoughnodirectevidenceexistsofsucheffectsinwomenreceivingantiepilepticdrugs,womenshouldbeadvisedtostarttakingfolicacidsupplementation(5mg)assoonascontraceptionisdiscontinued.

Theavailableevidencesuggeststhatanticonvulsantsmonotherapyispreferred.Dosageshouldbereviewedbeforeconceptionandthelowesteffectivedoseused,individeddoses,asabnormalpregnancyoutcometendstobeassociatedwithhighertotaldailydosageandwiththesizeofanindividualdose.Theincidenceofneuraltubedefectsriseswithincreasingdosage,particularlyabove1000mgdaily.Theadministrationinseveraldivideddosesoverthedayandtheuseofaprolongedreleaseformulationispreferableinordertoavoidhighpeakplasmalevels.

Duringpregnancy,Episenta®antiepileptictreatmentshouldnotbediscontinuedifithasbeeneffective.Nevertheless,specialistprenatalmonitoringshouldbeinstitutedinordertodetectthepossibleoccurrenceofaneuraltubedefectoranyothermalformation.Pregnanciesshouldbecarefullyscreenedbyultrasound,andothertechniquesifappropriate(seesection4.4Specialwarningsandspecialprecautionsforuse).

Manic episodes in bipolar disorder

Thismedicineshouldnotbeusedduringpregnancyandinwomenofchild-bearingpotentialunlessclearlynecessary(i.e.insituationswhereothertreatmentsareineffectiveornottolerated).Womenofchild-bearingpotentialhavetouseeffectivecontraceptionduringtreatment.

Risk in the neonate

Veryrarecasesofhaemorrhagicsyndromehavebeenreportedinneonateswhosemothershavetakenvalproateduringpregnancy.Thishaemorrhagicsyndromeisrelatedtohypofibrinogenaemia;afibrinogenaemiahasalsobeenreportedandmaybefatal.Thesearepossiblyassociatedwithadecreaseofcoagulationfactors.However,thissyndromehastobedistinguishedfromthedecreaseofthevitamin-Kfactorsinducedbyphenobarbitalandotherantiepilepticenzymeinducingdrugs.Thereforeplateletcount,fibrinogenplasmalevel,coagulationtestsandcoagulationfactorsshouldbeinvestigated in neonates.

100369 DESITIN Episenta 500mg SmPC AW.indd 9 02/08/2012 14:51

10

4.6.2 LactationExcretionofvalproateinbreastmilkislow,withaconcentrationbetween1to10%oftotal maternalserumlevels;uptonowchildrenbreastfedthathavebeenmonitoredduringtheneonatalperiodhavenotexperiencedclinicaleffects.AlthoughthereappearstobenocontraindicationstobreastfeedingbypatientsonEpisenta® physiciansareadvisedthatinanyindividualcase,considerationshouldbegiventothesafetyprofileofEpisenta®,specificallyhaematologicaldisorders(seesection4.8Undesirableeffects).

4.7 Effects on ability to drive and use machinesUseofEpisenta®mayprovideseizurecontrolsuchthatthepatientmaybeeligibletohold a driving licence.

Atthestartoftreatmentwithsodiumvalproate,athigherdosagesorwithacombinationofothercentrallyactingdrugs,reactiontimemaybealteredtoanextentthataffectstheabilitytodriveortooperatemachinery,irrespectiveoftheeffectontheprimarydiseasebeingtreated.Patientsshouldbewarnedoftheriskoftransientdrowsiness.Thisisespeciallythecasewhentakenduringanticonvulsantpolytherapy,concomitantuseofbenzodiazepinesorincombinationwithalcohol.

4.8 Undesirable effectsCongenitalandfamilial/geneticdisorders:(seesection4.6Pregnancyandlactation).

Hepato-biliary disorders:Rarecasesofhepaticdysfunction(seesection4.4Specialwarningsandprecautionsforuse).Severeliverdamage,includinghepaticfailuresometimesresultinginfatalities,hasbeenreported(seesections4.2Posologyandmethodofadministration,4.3Contraindicationsand4.4Specialwarningsandprecautionsforuse).Increasedliverenzymesarecommon,particularlyearlyintreatment,andmaybetransient(seesection4.4Specialwarningsandprecautionsforuse).

Gastro-intestinal disorders: (nausea, gastralgia, diarrhoea)Frequentlyoccuratthestartofthetreatment,buttheyusuallydisappearafterafewdayswithoutdiscontinuingtreatment.TheseproblemscanusuallybeovercomebytakingEpisenta®withorafter food.

Veryrarecasesofpancreatitis,sometimesfatal,havebeenreported(seesection4.4Specialwarningsandprecautionsforuse).

Nervous system disorders:Sedationhasbeenreportedoccasionally,usuallywhenincombinationwithotheranticonvulsants. Inmonotherapyitoccurredearlyintreatmentonrareoccasionsandisusuallytransient.Rarecasesoflethargyoccasionallyprogressingtostupor,sometimeswithassociatedhallucinationsorconvulsionshavebeenreported.Encephalopathyandcomahaveveryrarelybeenobserved.Thesecaseshaveoftenbeenassociatedwithatoohighstartingdoseoratoorapiddoseescalationorconcomitantuseofotheranticonvulsants,notablyphenobarbitalortopiramate.Theyhaveusuallybeenreversibleonwithdrawalof treatment or reduction of dosage.

100369 DESITIN Episenta 500mg SmPC AW.indd 10 02/08/2012 14:51

11

Veryrarecasesofreversibleextrapyramidalsymptomsincludingparkinsonism,orreversibledementiaassociatedwithreversiblecerebralatrophyhavebeenreported.Doserelatedataxiaandfineposturaltremorhaveoccasionallybeenreported.

Anincreaseinalertnessmayoccur,thisisgenerallybeneficialbutoccasionallyaggression,hyperactivityandbehaviouraldeteriorationhavebeenreported.

Metabolic disorders:Casesofisolatedandmoderatehyperammonaemiawithoutchangeinliverfunctiontestsmayoccurfrequently,areusuallytransientandshouldnotcausetreatmentdiscontinuation.However,theymaypresentclinicallyasvomiting,ataxia,andincreasingcloudingofconsciousness.ShouldthesesymptomsoccurEpisenta®shouldbediscontinued.Veryrarecasesofhyponatraemiahavebeenreported.Hyperammonaemiaassociatedwithneurologicalsymptomshavealsobeenreported(seesection4.4Specialwarningsandprecautionsforuse).Insuchcasesfurtherinvestigationshouldbeconsidered.

Blood and lymphatic system disorders:Frequentoccurrenceofthrombocytopenia,rarecasesofanaemia,leucopeniaorpanocytopenia. Thebloodpicturereturnedtonormalwhenthedrugwasdiscontinued.

Bone marrow failure, including red cell aplasia.

Agranulocytosis.

Isolatedreductioninbloodfibrinogenand/oranincreaseinprothrombintimehavebeenreported,usuallywithoutassociatedclinicalsignsandparticularlywithhighdoses(sodiumvalproatehasaninhibitoryeffectonthesecondphaseofplateletaggregation).Spontaneousbruisingorbleeding isanindicationofwithdrawalofmedicationpendinginvestigations(seesection4.6Pregnancy andlactation).

Skin and subcutaneous disorders:Rashrarelyoccurswithsodiumvalproate.Inveryrarecases,toxicepidermalnecrolysis,Stevens-Johnsonsyndromeanderythemamultiformehavebeenreported.Transienthairloss,whichmaysometimesbedose-related,hasoftenbeenreported.Regrowthnormallybeginswithin6months,althoughthehairmaybecomemorecurlythanpreviously.Hirsutismandacnehavebeenveryrarelyreported.

Musculoskeletal and connective tissue disordersTherehavebeenreportsofdecreasedbonemineraldensity,osteopenia,osteoporosisandfracturesinpatientsonlong-termtherapywithsodiumvalproate.Themechanismbywhichsodiumvalproateaffectsbonemetabolismhasnotbeenidentified.

Reproductive system and breast disorders:Amenorrhoeaandirregularperiodshavebeenreported.Veryrarelygynaecomastiahasoccurred.

Vascular disorders:Theoccurrenceofvasculitishasoccasionallybeenreported.

Ear disorders:Hearingloss,eitherreversibleorirreversiblehasbeenreportedrarely;howeveracauseandeffectrelationshiphasnotbeenestablished.

100369 DESITIN Episenta 500mg SmPC AW.indd 11 02/08/2012 14:51

12

Renal and urinary disorders:TherehavebeenisolatedreportsofreversibleFanconi’ssyndrome(adefectinproximalrenal tubularfunctiongivingrisetoglycosuria,aminoaciduria,phospaturia,anduricosuria)associated withsodiumvalproatetherapy,butthemodeofactionisasyetunclear.Veryrarecasesofenuresis havebeenreported.

Immune system disorders:Angioedema,DrugRashwithEosinophilia,SystemicSymptoms(DRESS)syndromeandallergicreactions(rangingfromrashtohypersensitivityreaction)havebeenreported.

General disorders:Veryrarecasesofnon-severeperipheraloedemahavebeenreported.

Increaseinweightmayalsooccur.Weightgainbeingariskfactorforpolycysticovarysyndrome, itshouldbecarefullymonitored(seesection4.4Specialwarningsandprecautionsforuse).

4.9 OverdoseCasesofaccidentalanddeliberateoverdosagewithoraltherapyhavebeenreported.Atplasmaconcentrationsofupto5to6timesthemaximumtherapeuticlevels,thereareunlikelytobeanysymptomsotherthannausea,vomitinganddizziness.Inmassiveoverdose,10to20timesthemaximumtherapeuticlevels,theremaybeseriousCNSdepressionorcomawithmuscularhypotonia,hyporeflexia,miosis,impairedrespiratoryfunction,metabolicacidosis.Afavourableoutcomeisusual,however some deaths have occurred following massive overdose.

Thesymptomsmayhoweverbevariableandseizureshavebeenreportedinthepresenceofveryhighplasmalevels.Casesofintracranialhypertensionrelatedtocerebraloedemahavebeenreported. Anumberofdeathshaveoccurredfollowinglargeoverdoses.Hospitalmanagementofoverdoseincludes induced vomiting, gastric lavage, assisted ventilation and other supportive measures. Haemodialysisandhaemoperfusionhavebeenusedsuccessfully.Intravenousnaloxonehasalsobeenusedsometimesinassociationwithactivatedcharcoalgivenorally.

100369 DESITIN Episenta 500mg SmPC AW.indd 12 02/08/2012 14:51

13

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic propertiesPharmacotherapeuticGroup:Fattyacidderivatives ATCno:N03AG01

Themodeofactionofvalproicacidisnotfullyunderstoodbutmayinvolveanelevationofgamma-aminobutyricacidlevelsinthebrain.

Incertainin-vitrostudies,itwasreportedthatsodiumvalproatecouldstimulateHIVreplication,butstudiesonperipheralbloodmononuclearcellsfromHIV-infectedsubjectsshowthatsodiumvalproatedoesnothaveamitogen-likeeffectoninducingHIVreplication.Indeed,theeffectofsodiumvalproateonHIVreplicationex-vivoishighlyvariable,modestinquantity,appearstobeunrelatedtothedoseandhasnotbeendocumentedinman.

5.2 Pharmacokinetic propertiesWithperoraladministration90-100%ofthedoseisrapidlyabsorbed.

MaximalplasmaconcentrationisachievedwithEpisenta®within6.5±3.3hours.Thehalf-lifeis 12-16hinmostpatientsbutcaninexceptionalcasesbeconsiderablylower.Impairedrenalfunctionprolongsthehalf-life.Ininfantsunder2monthsthehalf-lifecanbeprolongedupto60hoursbut in older children it is the same as in adults.

Steady-stateconcentrationisnormallyachievedaftertreatmentin3-5days.Asatisfactoryeffectismostoftenachievedat50–100µg/ml,butthepatient’soverallsituationmustbeconsidered.

Therelationbetweenthedoseandeffect,andbetweenplasmaconcentrationsandeffect,hasnotbeenfullyclarified.TheCSFconcentrationisupto10%oftheplasmaconcentration.About90%ofsodiumvalproateisboundtoplasmaprotein,whichmayentailariskofclinicallysignificantinteractionswithotherantiepileptics,primarilyphenytoin.Sodiumvalproateismetabolisedtoagreatextentandisexcretedintheurineasconjugatedmetabolites.Sodiumvalproatecrossestheplacentalbarrierandconcentrationsoffoetalplasmaarecomparabletothoseinthemother.

Valproicacidpassesintobreastmilkbutisnotlikelytoinfluencethechildwhentherapeuticdoses are used.

5.3 Preclinical safety dataTherearenopreclinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedin other sections of the SPC.

100369 DESITIN Episenta 500mg SmPC AW.indd 13 02/08/2012 14:51

14

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipientsProlonged-release granule: calcium stearate silicondioxide(methylated) ammoniomethacrylatecopolymertypeB sodiumlaurylsulfate polysorbate80

Granule coating: ethylcellulose dibutylsebacate oleic acid

6.2 IncompatibilitiesNoneknown.

6.3 Shelf life36months.

6.4 Special precautions for storageDonotstoreabove30°C.Storeintheoriginalcontainer.Keepthecontainertightlyclosed.

6.5 Nature and contents of container50,100or200Claycoatedkraftpaper/Aluminium/PEsachets.

6.6 Special precautions for disposalNone.

100369 DESITIN Episenta 500mg SmPC AW.indd 14 02/08/2012 14:51

15

7 MARKETING AUTHORISATION HOLDERDesitinArzneimittelGmbH WegbeimJäger214 D-22335Hamburg Germany

8 MARKETING AUTHORISATION NUMBER(S)PL14040/0026

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION6thOctober2006.

10 DATE OF REVISION OF THE TEXT28thMarch2012.

100369 DESITIN Episenta 500mg SmPC AW.indd 15 02/08/2012 14:51

16

3000,CathedralHillIndustrialEstate, Guildford,Surrey,GU27YBTel:+44(0)1483246455

MedicalEnquiry:MedInfo@desitin.co.uk

UK/EP/12/0006Dateorpreparation:July2012

100369 DESITIN Episenta 500mg SmPC AW.indd 16 02/08/2012 14:51