EPANUTIN

Main information

  • Trade name:
  • EPANUTIN Oral Suspension 30 MG/ 5ml
  • Dosage:
  • 30 MG/ 5ml
  • Pharmaceutical form:
  • Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPANUTIN Oral Suspension 30 MG/5ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/051/003
  • Authorization date:
  • 16-09-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epanutin30mg/5mlOralSuspension

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlofsuspensioncontains30mgPhenytoin

Each5mlalsocontains1.044gSucrose,24.66microlitresEthanol,0.316mgCarmoisine(E122),0.1mgSunset

YellowFCF(E110).

Forafulllistofexcipientssee6.1.

3PHARMACEUTICALFORM

Oralsuspension.

ProductimportedfromtheUK:

Viscouscherryredcolouredoralsuspension.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Controloftonic-clonicseizures(grandmalepilepsy),partialseizures(focalincludingtemporallobe)oracombination

ofthese,andthepreventionandtreatmentofseizuresoccurringduringorfollowingneurosurgeryand/orseverehead

injury.Epanutinhasalsobeenemployedinthetreatmentoftrigeminalneuralgiabutitshouldonlybeusedassecond

linetherapyifcarbamazepineisineffectiveorpatientsareintoleranttocarbamazepine.

4.2Posologyandmethodofadministration

Fororaladministrationonly.

Dosage:

Dosageshouldbeindividualizedastheremaybewideinterpatientvariabilityinphenytoinserumlevelswithequivalent

dosage.Epanutinshouldbeintroducedinsmalldosageswithgradualincrementsuntilcontrolisachievedoruntiltoxic

effectsappear.Insomecasesserumleveldeterminationsmaybenecessaryforoptimaldosageadjustments–the

clinicallyeffectivelevelisusually10–20mg/l(40–80micromoles/l)althoughsomecasesoftonic-clonicseizures

maybecontrolledwithlowerserumlevelsofphenytoin.Withrecommendeddosageaperiodofseventotendaysmay

berequiredtoachievesteadystateserumlevelswithEpanutinandchangesindosageshouldnotbecarriedoutat

intervalsshorterthanseventotendays.Maintenanceoftreatmentshouldbethelowestdoseofanticonvulsant

consistentwithcontrolofseizures.

EpanutinCapsules,OralSuspensionandInfatabs:

EpanutinCapsulescontainphenytoinsodiumwhereasEpanutinOralSuspensionandEpanutinInfatabscontain

phenytoin.Although100mgofphenytoinsodiumisequivalentto92mgofphenytoinonamolecularweightbasis,

thesemolecularequivalentsarenotnecessarilybiologicallyequivalent.Physiciansshouldthereforeexercisecarein

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Adults:

Initially3to4mg/kg/daywithsubsequentdosageadjustmentifnecessary.Formostadultsasatisfactorymaintenance

dosewillbe200to500mgdailyinsingleordivideddoses.Exceptionally,adailydoseoutsidetherangemaybe

indicated.Dosageshouldnormallybeadjustedaccordingtoserumlevelswhereassayfacilitiesexist.

Elderly:

Elderly(over65years):AswithadultsthedosageofEpanutinshouldbetitratedtothepatient’sindividual

requirementsusingthesameguidelines.Aselderlypatientstendtoreceivemultipledrugtherapies,thepossibilityof

druginteractionsshouldbeborneinmind.

InfantsandChildren:

Initially,5mg/kg/dayintwodivideddoses,withsubsequentdosageindividualisedtoamaximumof300mgdaily.A

recommendeddailymaintenancedosageisusually4-8mg/kg.

Neonates:

Theabsorptionofphenytoinfollowingoraladministrationinneonatesisunpredictable.Furthermore,themetabolismof

phenytoinmaybedepressed.Itisthereforeespeciallyimportanttomonitorserumlevelsintheneonate.

4.3Contraindications

Phenytoiniscontraindicatedinthosepatientswhoarehypersensitivetophenytoin,oritsinactiveingredients,orother

hydantoins.

4.4Specialwarningsandprecautionsforuse

Suicidalideationandbehaviourhavebeenreportedinpatientstreatedwithanti-epilepticagentsinseveralindications.

Ameta-analysisofrandomisedplacebocontrolledtrialsofanti-epilepticdrugshasalsoshownasmallincreasedriskof

suicidalideationandbehaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethe

possibilityofanincreasedriskforphenytoin.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

Abruptwithdrawalofphenytoininepilepticpatientsmayprecipitatestatusepilepticus.When,inthejudgementofthe

clinician,theneedfordosagereduction,discontinuation,orsubstitutionofalternativeanti-epilepticmedicationarises,

thisshouldbedonegradually.

However,intheeventofanallergicorhypersensitivityreaction,rapidsubstitutionofalternativetherapymaybe

necessary.Inthiscase,alternativetherapyshouldbeananti-epilepticdrugnotbelongingtothehydantoinchemical

class.

Phenytoinishighlyproteinboundandextensivelymetabolisedbytheliver.Reduceddosagetopreventaccumulation

andtoxicitymaythereforeberequiredinpatientswithimpairedliverfunction.Whereproteinbindingisreduced,asin

uraemia,totalserumphenytoinlevelswillbereducedaccordingly.However,thepharmacologicallyactivefreedrug

concentrationisunlikelytobealtered.Therefore,underthesecircumstancestherapeuticcontrolmaybeachievedwith

totalphenytoinlevelsbelowthenormalrangeof10-20mg/l(40-80micromoles/l).Patientswithimpairedliver

function,elderlypatientsorthosewhoaregravelyillmayshowearlysignsoftoxicity.

Phenytoinisnoteffectiveforabsence(petitmal)seizures.Iftonic-clonic(grandmal)andabsenceseizuresarepresent

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Phenytoinmayaffectglucosemetabolismandinhibitinsulinrelease.Hyperglycaemiahasbeenreportedinassociation

withtoxiclevels.Phenytoinisnotindicatedforseizuresduetohypoglycaemiaorothermetaboliccauses.

Serumlevelsofphenytoinsustainedabovetheoptimalrangemayproduceconfusionalstatesreferredtoas"delirium",

"psychosis",or"encephalopathy",orrarelyirreversiblecerebellardysfunction.Accordingly,atthefirstsignofacute

toxicity,serumdrugleveldeterminationsarerecommended.Dosereductionofphenytointherapyisindicatedifserum

levelsareexcessive;ifsymptomspersist,terminationoftherapywithphenytoinisrecommended.

HerbalpreparationscontainingSt.John’sWort(Hypericumperforatum)shouldnotbeusedwhiletakingphenytoindue

totheriskofdecreasedplasmaconcentrationsandreducedclinicaleffectsofphenytoin(seeSection4.5).

AnticonvulsantHypersensitivitySyndrome(AHS)isararedruginduced,multiorgansyndromewhichispotentially

fatalandoccursinsomepatientstakinganticonvulsantmedication.Itischaracterizedbyfever,rash,lymphadenopathy,

andothermultiorganpathologies,oftenhepatic.Themechanismisunknown.Theintervalbetweenfirstdrugexposure

andsymptomsisusually2-4weeksbuthasbeenreportedinindividualsreceivinganticonvulsantsfor3ormore

months.

PatientsathigherriskfordevelopingAHSincludeblackpatients,patientswhohaveafamilyhistoryoforwhohave

experiencedthissyndromeinthepast,andimmunosuppressedpatients.Thesyndromeismoresevereinpreviously

sensitizedindividuals.IfapatientisdiagnosedwithAHS,discontinuethephenytoinandprovideappropriate

supportivemeasures.

IntegumentaryEffect

Phenytoincancauserare,seriousskinadverseeventssuchasexfoliativedermatitis,Stevens-JohnsonSyndrome(SJS),

andtoxicepidermalnecrolysis(TEN),whichcanbefatal.Althoughseriousskinreactionsmayoccurwithoutwarning,

patientsshouldbealertforthesignsandsymptomsofskinrashandblisters,fever,orothersignshypersensitivitysuch

asitching,andshouldseekmedicaladvicefromtheirphysicianimmediatelywhenobservinganyindicativesignsor

symptoms.Thephysicianshouldadvisethepatienttodiscontinuetreatmentiftherashappears.Iftherashisofamilder

type(measles-likeorscarlatiniform),therapymayberesumedaftertherashhascompletelydisappeared.Iftherash

recursuponreinstitutionoftherapy,furtherphenytoinmedicationiscontraindicated.Publishedliteraturehassuggested

thattheremaybeanincreased,althoughstillrare,riskofhypersensitivityreactions,includingskinrash,SJS,TEN,

hepatotoxicity,andAnticonvulsantHypersensitivitySyndromeinblackpatients.

StudiesinpatientsofChineseancestryhavefoundastrongassociationbetweentheriskofdevelopingSJS/TENand

thepresenceofHLA-B*1502,aninheritedallelicvariantoftheHLABgene,inpatientsusingcarbamazepine.HLA-B*

1502maybeassociatedwithincreasedriskofdevelopingSJS/TENinpatientsofThaiandHanChineseancestry

takingdrugsassociatedwithSJS/TEN,includingphenytoin.IfthesepatientsareknowntobepositiveforHLA-

B*1502,theuseofPhenytoinshouldonlybeconsideredifthebenefitsarethoughttoexceedtherisks.

IntheCaucasianandJapanesepopulation,thefrequencyofHLAB*1502alleleisextremelylow,andthusitisnot

possibleatpresenttoconcludeonriskassociation.Adequateinformationaboutriskassociationinotherethnicitiesis

currentlynotavailable.

MusculoskeletalEffect

PhenytoinandotheranticonvulsantsthathavebeenshowntoinducetheCYP450enzymearethoughttoaffectbone

mineralmetabolismindirectlybyincreasingthemetabolismofVitaminD3.ThismayleadtoVitaminDdeficiencyand

heightenedriskofosteomalacia,bonefractures,osteoporosis,hypocalcemia,andhypophosphatemiainchronically

treatedepilepticpatients.

Inviewofisolatedreportsassociatingphenytoinwithexacerbationofporphyria,cautionshouldbeexercisedinusing

themedicationinpatientssufferingfromthisdisease.

Phenytoinmaycauseloweredserumlevelsoffolicacid.Itisrecommendedthatserumfolateconcentrationsbe

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Thismedicinalproductcontainssmallamountsofethanol(alcohol),lessthan100mgperdose.

Epanutincontainssucrose,atypeofsugar.Ifyouhavebeentoldthatyouhaveanintolerancetosomesugars,contact

yourdoctorbeforetakingthismedicinalproduct.Thismedicinemaybeharmfultotheteeth.

Thismedicinecontainsazocolouringagents(E110andE112)thatmaycauseallergicreactions.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Drugswhichmayincreasephenytoinserumlevelsinclude:

Amiodarone,antifungalagents(suchas,butnotlimitedto,amphotericinB,fluconazole,ketoconazole,miconazoleand

itraconazole),chloramphenicol,chlordiazepoxide,diazepam,dicoumarol,diltiazem,disulfiram,fluoxetine,

fluvoxamine,sertraline,H-antagonistse.g.cimetidine,halothane,isoniazid,methylphenidate,nifedipine,omeprazole,

oestrogens,phenothiazines,phenylbutazone,salicylates,succinimides,sulphonamides,tolbutamide,trazodoneand

viloxazine.

Drugswhichmaydecreasephenytoinserumlevelsinclude:

Folicacid,reserpine,rifampicin,sucralfate,theophyllineandvigabatrin.

SerumlevelsofphenytoincanbereducedbyconcomitantuseoftheherbalpreparationscontainingStJohn’sWort

(Hypericumperforatum).ThisisduetoinductionofdrugmetabolisingenzymesbySt.John’sWort.Herbal

preparationscontainingSt.John’sWortshouldthereforenotbecombinedwithaphenytoin.Theinducingeffectmay

persistforatleast2weeksaftercessationoftreatmentwithSt.John’sWort.IfapatientisalreadytakingSt.John’s

WortchecktheanticonvulsantlevelsandstopSt.John’sWort.AnticonvulsantlevelsmayincreaseonstoppingSt.

John’sWort.Thedoseofanticonvulsantmayneedadjusting.

Apharmacokineticinteractionstudybetweennelfinavirandphenytoinbothadministeredorallyshowedthatnelfinavir

reducedAUCvaluesofphenytoin(total)andfreephenytoinby29%and28%,respectively.Therefore,phenytoin

concentrationshouldbemonitoredduringco-administrationwithnelfinavir,asnelfinavirmayreducephenytoinplasma

concentration(seesection5.2PharmacokineticProperties–PharmacokineticInteraction).

Drugswhichmayeitherincreaseordecreasephenytoinserumlevelsinclude:

Carbamazepine,phenobarbital,valproicacid,sodiumvalproate,antineoplasticagents,certainantacidsand

ciprofloxacin.Similarly,theeffectofphenytoinoncarbamazepine,phenobarbital,valproicacidandsodiumvalproate

serumlevelsisunpredictable.

Acutealcoholintakemayincreasephenytoinserumlevelswhilechronicalcoholismmaydecreaseserumlevels.

Althoughnotatruepharmacokineticinteraction,tricylicantidepressantsandphenothiazinesmayprecipitate

seizuresinsusceptiblepatientsandphenytoindosagemayneedtobeadjusted.

Drugswhoseeffectisimpairedbyphenytoininclude:

Antifungalagents(e.g.azoles),antineoplasticagents(e.g.teniposade),calciumchannelblockers,clozapine,

corticosteroids,ciclosporin,dicoumarol,digitoxin,doxycycline,furosemide,lamotrigine,methadone,neuromuscular

blockers,oestrogens,oralcontraceptives,paroxetine,sertraline,quinidine,rifampicin,theophyllineandvitaminD.

Drugswhoseeffectisalteredbyphenytoininclude:

Warfarin.Theeffectofphenytoinonwarfarinisvariableandprothrombintimesshouldbedeterminedwhenthese

agentsarecombined.

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Drug-EnteralFeeding/NutritionalPreparationsInteraction:

Literaturereportssuggestthatpatientswhohavereceivedenteralfeedingpreparationsand/orrelatednutritional

supplementshavelowerthanexpectedphenytoinplasmalevels.Itisthereforesuggestedthatphenytoinnotbe

administeredconcomitantlywithanenteralfeedingpreparation.

Morefrequentserumphenytoinlevelmonitoringmaybenecessaryinthesepatients.

Drug/LaboratoryTestInteractions:

Phenytoinmaycauseaslightdecreaseinserumlevelsoftotalandfreethyroxine,possiblyasaresultofenhanced

peripheralmetabolism.Thesechangesdonotleadtoclinicalhypothyroidismanddonotaffectthelevelsof

circulatingTSH.Thelattercanthereforebeusedfordiagnosinghypothyroidisminthepatientonphenytoin.

Phenytoindoesnotinterferewithuptakeandsuppressiontestsusedinthediagnosisofhypothyroidism.Itmay,

however,producelowerthannormalvaluesfordexamethasoneormetapyronetests.Phenytoinmaycauseraised

serumlevelsofglucose,alkalinephosphatase,andgammaglutamyltranspeptidaseandloweredserumlevelsof

calciumandfolicacid.Itisrecommendedthatserumfolateconcentrationsbemeasuredatleastonceevery6

months,andfolicacidsupplementsgivenifnecessary.Phenytoinmayaffectbloodsugarmetabolismtests.

4.6Fertility,pregnancyandlactation

Thereareintrinsicmethodologicproblemsinobtainingadequatedataondrugteratogenicityinhumans.Geneticfactors

orepilepticconditionitselfmaybemoreimportantthandrugtherapyinleadingtobirthdefects.Thegreatmajorityof

mothersonanticonvulsantmedicationdelivernormalinfants.Itisimportanttonotethatanticonvulsantdrugsshould

notbediscontinuedinpatientsinwhomthedrugisadministeredtopreventmajorseizuresbecauseofthestrong

possibilityofprecipitatingstatusepilepticuswithattendanthypoxiaandthreattolife.Inindividualcaseswherethe

severityandfrequencyoftheseizuredisorderaresuchthattheremovalofmedicationdoesnotposeaseriousthreatto

thepatient,discontinuationofthedrugmaybeconsideredpriororandduringpregnancyalthoughitcannotbesaid

withanyconfidencethatevenminorseizuresdonotposesomehazardtothedevelopingembryoorfoetus.

Anticonvulsantsincludingphenytoinmayproducecongenitalabnormalitiesintheoffspringofasmallnumberof

epilepticpatients.Theexactroleofdrugtherapyintheseabnormalitiesisunclearandgeneticfactors,insomestudies,

havealsobeenshowntobeimportant.Epanutinshouldbeusedduringpregnancy,especiallyearlypregnancy,ifinthe

judgementofthephysicianthepotentialbenefitsclearlyoutweightherisk.

Inadditiontothereportsofincreasedincidenceofcongenitalmalformations,suchascleftlip/palateandheart

malformationsinchildrenofwomenreceivingphenytoinandotherantiepilepticdrugs,therehavemorerecentlybeen

reportsofafoetalhydantoinsyndrome.Thisconsistsofprenatalgrowthdeficiency,micro-encephalyandmental

deficiencyinchildrenborntomotherswhohavereceivedphenytoin,barbiturates,alcohol,ortrimethadione.

However,thesefeaturesareallinterrelatedandarefrequentlyassociatedwithintrauterinegrowthretardationfrom

othercauses.

Therehavebeenisolatedreportsofmalignancies,includingneuroblastoma,inchildrenwhosemothersreceived

phenytoinduringpregnancy.

Anincreaseinseizurefrequencyduringpregnancyoccursinaproportionofpatients,andthismaybeduetoaltered

phenytoinabsorptionormetabolism.Periodicmeasurementofserumphenytoinlevelsisparticularlyvaluableinthe

managementofapregnantepilepticpatientasaguidetoanappropriateadjustmentofdosage.However,postpartum

restorationoftheoriginaldosagewillprobablybeindicated.

Neonatalcoagulationdefectshavebeenreportedwithinthefirst24hoursinbabiesborntoepilepticmothersreceiving

phenytoin.VitaminK1hasbeenshowntopreventorcorrectthisdefectandmaybegiventothemotherbeforedelivery

andtotheneonateafterbirth.

Infantbreastfeedingisnotrecommendedforwomentakingphenytoinbecausephenytoinappearstobesecretedinlow

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4.7Effectsonabilitytodriveandusemachines

Patientsshouldbeadvisednottodriveacaroroperatepotentiallydangerousmachineryuntilitisknownthatthis

medicationdoesnotaffecttheirabilitytoengageintheseactivities.

4.8Undesirableeffects

Immunesystemreactions:Anaphylactoidreactionandanaphylaxis

CentralNervousSystem

Themostcommonmanifestationsencounteredwithphenytointherapyarereferabletothissystemandareusually

dose-related.Theseincludenystagmus,ataxia,slurredspeech,decreasedco-ordination,mentalconfusion,

paraesthesia,somnolence,drowsinessandvertigo.

Dizziness,insomnia,transient,nervousness,motortwitching,tasteperversionandheadacheshavealsobeenobserved.

Therehavealsobeenrarereportsofphenytoininduceddyskinesias,includingchorea,dystonia,tremorandasterixis,

similartothoseinducedbyphenothiazineandotherneurolepticdrugs.

Thereareoccasionalreportsofirreversiblecerebellardysfunctionassociatedwithseverephenytoinoverdosage.A

predominantlysensoryperipheralpolyneuropathyhasbeenobservedinpatientsreceivinglong-termphenytointherapy.

Gastrointestinal

Nausea,vomitingandconstipation,toxichepatitis,andliverdamage.

Dermatological

Dermatologicalmanifestationssometimesaccompaniedbyfeverhaveincludedscarlatiniformormorbilliformrashes.A

morbilliformrashisthemostcommon;dermatitisisseenmorerarely.Othermoreseriousandrareformshaveincluded

bullous,exfoliativeorpurpuricdermatitis,lupuserythematosus,Stevens-Johnsonsyndromeandtoxicepidermal

necrolysis(seeSection4.4).

ConnectiveTissue

Coarseningofthefacialfeatures,enlargementofthelips,gingivalhyperplasia,hirsutism,hypertrichosis,Peyronie's

DiseaseandDupuytren'scontracturemayoccurrarely.

Haemopoietic

Haemopoieticcomplications,somefatal,haveoccasionallybeenreportedinassociationwithadministrationof

phenytoin.Thesehaveincludedthrombocytopenia,leucopenia,granulocytopenia,agranulocytosis,pancytopeniawithor

withoutbonemarrowsuppression,andaplasticanaemia.Whilemacrocytosisandmegaloblasticanaemiahaveoccurred,

theseconditionsusuallyrespondtofolicacidtherapy.

Therehavebeenanumberofreportssuggestingarelationshipbetweenphenytoinandthedevelopmentof

lymphadenopathy(localandgeneralised)includingbenignlymphnodehyperplasia,pseudolymphoma,lymphoma,and

Hodgkin'sDisease.Althoughacauseandeffectrelationshiphasnotbeenestablished,theoccurrenceof

lymphadenopathyindicatestheneedtodifferentiatesuchaconditionfromothertypesoflymphnodepathology.Lymph

nodeinvolvementmayoccurwithorwithoutsymptomsandsignsresemblingserumsickness,eg.fever,rashandliver

involvement.

Inallcasesoflymphadenopathy,follow-upobservationforanextendedperiodisindicatedandeveryeffortshouldbe

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Frequentbloodcountsshouldbecarriedoutduringtreatmentwithphenytoin.

ImmuneSystem

Hypersensitivitysyndromehasbeenreportedandmayinrarecasesbefatal(thesyndromemayinclude,butisnot

limitedto,symptomssuchasarthralgias,eosinophilia,fever,liverdysfunction,lymphadenopathyorrash),systemic

lupuserythematosus,polyarteritisnodosa,andimmunoglobulinabnormalitiesmayoccur.

Severalindividualcasereportshavesuggestedthattheremaybeanincreased,althoughstillrare,incidenceof

hypersensitivityreactions,includingskinrashandhepatotoxicity,inblackpatients.

Other

Polyarthropathy,interstitialnephritis,pneumonitis.

Post-marketingexperience

MusculoskeletalSystem

Bonefracturesandosteomalaciahavebeenassociatedwithlongterm(>10years)useofphenytoinbypatientswithchronic

epilepsy.Osteoporosisandotherdisordersofbonemetabolismsuchashypocalcemia,hypophophatemiaanddecreased

levelsofVitaminDmetaboliteshavealsobeenreported.

4.9Overdose

Thelethaldoseinchildrenisnotknown.Themeanlethaldoseforadultsisestimatedtobe2to5g.Theinitial

symptomsarenystagmus,ataxiaanddysarthria.Thepatientthenbecomescomatose,thepupilsareunresponsiveand

hypotensionoccursfollowedbyrespiratorydepressionandapnoea.Deathisduetorespiratoryandcirculatory

depression.

Therearemarkedvariationsamongindividualswithrespecttophenytoinserumlevelswheretoxicitymayoccur.

Nystagmusonlateralgazeusuallyappearsat20mg/l,andataxiaat30mg/l,dysarthriaandlethargyappearwhenthe

serumconcentrationisgreaterthan40mg/l,butaconcentrationashighas50mg/lhasbeenreportedwithoutevidenceof

toxicity.

Asmuchas25timestherapeuticdosehasbeentakentoresultinserumconcentrationover100mg/l(400micromoles/l)

withcompleterecovery.

Treatment

Treatmentisnon-specificsincethereisnoknownantidote.Ifingestedwithintheprevious4hoursthestomachshould

beemptied.Ifthegagreflexisabsent,theairwayshouldbesupported.Oxygenandassistedventilationmaybe

necessaryforcentralnervoussystem,respiratoryandcardiovasculardepression.Haemodialysiscanbeconsideredsince

phenytoinisnotcompletelyboundtoplasmaproteins.Totalexchangetransfusionhasbeenutilisedinthetreatmentof

severeintoxicationinchildren.

InacuteoverdosagethepossibilityofthepresenceofotherCNSdepressants,includingalcohol,shouldbebornein

mind.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Phenytoiniseffectiveinvariousanimalmodelsofgeneralisedconvulsivedisorders,reasonablyeffectiveinmodelsof

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Itappearstostabiliseratherthanraisetheseizurethresholdandpreventsspreadofseizureactivityratherthanabolish

theprimaryfocusofseizuredischarge.

Themechanismbywhichphenytoinexertsitsanticonvulsantactionhasnotbeenfullyelucidatedhowever,possible

contributoryeffectsinclude:

5.2Pharmacokineticproperties

Phenytoinisabsorbedfromthesmallintestineafteroraladministration.Variousformulationfactorsmayaffectthe

bioavailabilityofphenytoin;however,non-lineartechniqueshaveestimatedabsorptiontobeessentiallycomplete.

AfterabsorptionitisdistributedintobodyfluidincludingCSF.Itsvolumeofdistributionhasbeenestimatedtobe

between0.52and1.19litres/kg,anditishighlyproteinbound(usually90%inadults).

Theplasmahalf-lifeofphenytoininmanaverages22hourswitharangeof7to42hours.Steadystatetherapeuticdrug

levelsareachievedatleast7to10daysafterinitiationoftherapy.

Phenytoinishydroxylatedintheliverbyanenzymesystemwhichissaturable.Smallincrementaldosesmayproduce

verysubstantialincreasesinserumlevelswhentheseareintheupperrangeoftherapeuticconcentrations.

Theparameterscontrollingeliminationarealsosubjecttowideinterpatientvariation.Theserumlevelachievedbya

givendoseisthereforealsosubjecttowidevariation.

PharmacokineticInteraction

Co-administrationofnelfinavirtablets(1,250mgtwiceaday)withphenytoincapsule(300mgonceaday)didnot

changetheplasmaconcentrationofnelfinavir.However,coadministrationofnelfinavirreducedtheAUCvaluesof

phenytoin(total)andfreephenytoinby29%and28%,respectively(seesection4.5Interactionwithothermedicinal

productsandotherformsofinteraction).

5.3Preclinicalsafetydata

Pre-clinicalsafetydatadoesnotaddanythingoffurthersignificancetotheprescriber.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Aluminiummagnesiumsilicate

Sodiumbenzoate(E211)

Citricacidmonohydrate

Carmellosesodium

Glycerol

Polysorbate40

Sucrose

Ethanol

Vanillin

Bananaflavour

Orangeoil

Carmoisine(E122)

Sunsetyellow(E110)

Non-synapticeffectstoreducesodiumconductance,enhanceactivesodiumextrusion,

blockrepetitivefiringandreducepost-tetanicpotentiation.

Post-synapticactiontoenhancegaba-mediatedinhibitionandreduceexcitatory

synaptictransmission.

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthebottleorouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25˚C.Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Amberglassbottlewith3pieceplasticchildresistant,tamperevidentclosurefittedwithapolyethylenefacedliner

containing500ml.Inanoverlabelledcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Shakewellbeforeuse.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Oldham

Lancashire

OL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/51/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16thSeptember2011.

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