EPANUTIN

Main information

  • Trade name:
  • EPANUTIN Capsules Hard 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPANUTIN Capsules Hard 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/147/002
  • Authorization date:
  • 15-04-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epanutin100mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains100mgPhenytoinSodium

Eachcapsulealsocontainslactosemonohydrate

Forfulllistofexcipients,seeSection6.1

3PHARMACEUTICALFORM

Capsule,hard.

ProductimportedfromtheUK:

Halfwhiteandhalforangecapsulesmarkedwith“EPANUTIN100”containingawhitepowder.

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-clonicseizuresmay

becontrolledwithlowerserumlevelsofphenytoin.Withrecommendeddosageaperiodofseventotendaysmaybe

requiredtoachievesteadystateserumlevelswithEpanutinandchangesindosageshouldnotbecarriedoutatintervals

shorterthanseventotendays.Maintenanceoftreatmentshouldbethelowestdoseofanticonvulsantconsistentwith

controlofseizures.

EpanutinCapsules,SuspensionandInfatabs:

EpanutinCapsulescontainphenytoinsodiumwhereasEpanutinSuspensionandEpanutinInfatabscontainphenytoin.

Although100mgofphenytoinsodiumisequivalentto92mgofphenytoinonamolecularweightbasis,thesemolecular

equivalentsarenotnecessarilybiologicallyequivalent.

Physiciansshouldthereforeexercisecareinthosesituationswhereitisnecessarytochangethedosageformandserum

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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,rapidsubstitutionof

alternativetherapymaybenecessary.Inthiscase,alternativetherapyshouldbeananti-epilepticdrugnotbelongingto

thehydantoinchemicalclass.

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

together,combineddrugtherapyisneeded.

Phenytoinmayaffectglucosemetabolismandinhibitinsulinrelease.Hyperglycaemiahasbeenreportedinassociation

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Serumlevelsofphenytoinsustainedabovetheoptimalrangemayproduceconfusionalstatesreferredtoas"delirium",

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

toxicity,serumdrugleveldeterminationsarerecommended.Dosereductionofphenytointherapyisindicatedifserum

levelsareexcessive;ifsymptomspersist,terminationoftherapywithphenytoinisrecommended.

HerbalpreparationscontainingStJohn'swort(Hypericumperforatum)shouldnotbeusedwhiletakingphenytoindue

totheriskofdecreasedplasmaconcentrationsandreducedclinicaleffectsofphenytoin(seeSection4.5).

AnticonvulsantHypersensitivitySyndrome(AHS)isararedruginduced,multiorgansyndromewhichispotentially

fatalandoccursinsomepatientstakinganticonvulsantmedication.Itischaracterizedbyfever,rash,lymphadenopathy,

andothermultiorganpathologies,oftenhepatic.Themechanismisunknown.Theintervalbetweenfirstdrugexposure

andsymptomsisusually2-4weeksbuthasbeenreportedinindividualsreceivinganticonvulsantsfor3ormore

months.PatientsathigherriskfordevelopingAHSincludeblackpatients,patientswhohaveafamilyhistoryoforwho

haveexperiencedthissyndromeinthepast,andimmuno-suppressedpatients.Thesyndromeismoreseverein

previouslysensitizedindividuals.IfapatientisdiagnosedwithAHS,discontinuethephenytoinandprovide

appropriatesupportivemeasures.

IntegumentaryEffect

Phenytoincancauserare,seriousskinadverseeventssuchasexfoliativedermatitis,Stevens-JohnsonSyndrome(SJS),

andtoxicepidermalnecrolysis(TEN),whichcanbefatal.Althoughseriousskinreactionsmayoccurwithoutwarning,

patientsshouldbealertforthesignsandsymptomsofskinrashandblisters,fever,orothersignshypersensitivitysuch

asitching,andshouldseekmedicaladvicefromtheirphysicianimmediatelywhenobservinganyindicativesignsor

symptoms.Thephysicianshouldadvisethepatienttodiscontinuetreatmentiftherashappears.Iftherashisofa

mildertype(measles-likeorscarlatiniform),therapymayberesumedaftertherashhascompletelydisappeared.Ifthe

rashrecursuponreinstitutionoftherapy,furtherphenytoinmedicationiscontraindicated.Publishedliteraturehas

suggestedthattheremaybeanincreased,althoughstillrare,riskofhypersensitivityreactions,includingskinrash,SJS,

TEN,hepatotoxicity,andAnticonvulsantHypersensitivitySyndromeinblackpatients.

StudiesinpatientsofChineseancestryhavefoundastrongassociationbetweentheriskofdevelopingSJS/TENand

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

B*1502maybeassociatedwithincreasedriskofdevelopingSJS/TENinpatientsofThaiandHanChineseancestry

takingdrugsassociatedwithSJS/TEN,includingphenytoin.IfthesepatientsareknowntobepositiveforHLAB*1502,

theuseofPhenytoinshouldonlybeconsideredifthebenefitsarethoughttoexceedtherisks.

IntheCaucasianandJapanesepopulation,thefrequencyofHLAB*1502alleleisextremelylow,andthusitisnot

possibleatpresenttoconcludeonriskassociation.Adequateinformationaboutriskassociationinotherethnicitiesis

currentlynotavailable.

MusculoskeletalEffect

PhenytoinandotheranticonvulsantsthathavebeenshowntoinducetheCYP450enzymearethoughttoaffectbone

mineralmetabolismindirectlybyincreasingthemetabolismofVitaminD3.ThismayleadtoVitaminDdeficiencyand

heightenedriskofosteomalacia,bonefractures,osteoporosis,hypocalcemia,andhypophosphatemiainchronically

treatedepilepticpatients.

Inviewofisolatedreportsassociatingphenytoinwithexacerbationofporphyria,cautionshouldbeexercisedinusing

themedicationinpatientssufferingfromthisdisease.

Phenytoinmaycauseloweredserumlevelsoffolicacid.Itisrecommendedthatserumfolateconcentrationsbe

measuredatleastonceevery6months,andfolicacidsupplementsgivenifnecessary.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Drugswhichmayincreasephenytoinserumlevelsinclude:

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

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

fluvoxamine,sertraline,H-antagonists(e.g.cimetidine),halothane,isoniazid,methylphenidate,nifedipine,

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

trazodoneandviloxazine.

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,theeffectofphenytoinoncarbamazepinephenobarbital,valproicacidandsodiumvalproateserumlevelsis

unpredictable.

Acutealcoholintakemayincreasephenytoinserumlevelswhilechronicalcoholismmaydecreaseserumlevels.

Althoughnotatruepharmacokineticinteraction,tricylicantidepressantsandphenothiazinesmayprecipitate

seizuresinsusceptiblepatientsandphenytoindosagemayneedtobeadjusted.

Drugswhoseeffectisimpairedbyphenytoininclude:

Antifungalagents(e.g.azoles),antineoplasticagentse.g.teniposide,calciumchannelblockers,clozapine,

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

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

Drugswhoseeffectisalteredbyphenytoininclude:

Warfarin.Theeffectofphenytoinonwarfarinisvariableandprothrombintimesshouldbedeterminedwhenthese

agentsarecombined.

Serumleveldeterminationsareespeciallyhelpfulwhenpossibledruginteractionsaresuspected.

Drug/LaboratoryTestInteractions

Phenytoinmaycauseaslightdecreaseinserumlevelsoftotalandfreethyroxine,possiblyasaresultofenhanced

peripheralmetabolism.Thesechangesdonotleadtoclinicalhypothyroidismanddonotaffectthelevelsofcirculating

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Phenytoindoesnotinterferewithuptakeandsuppressiontestsusedinthediagnosisofhypothyroidism.Itmay,

however,producelowerthannormalvaluesfordexamethasoneormetapyronetests.Phenytoinmaycauseraisedserum

levelsofglucose,alkalinephosphatase,andgammaglutamyltranspeptidaseandloweredserumlevelsofcalciumand

folicacid.Itisrecommendedthatserumfolateconcentrationsbemeasuredatleastonceevery6months,andfolicacid

supplementsgivenifnecessary.Phenytoinmayaffectbloodsugarmetabolismtests.

4.6Fertility,pregnancyandlactation

Thereareintrinsicmethodologicproblemsinobtainingadequatedataondrugteratogenicityinhumans.Geneticfactors

ortheepilepticconditionitselfmaybemoreimportantthandrugtherapyinleadingtobirthdefects.Thegreatmajority

ofmothersonanticonvulsantmedicationdelivernormalinfants.Itisimportanttonotethatanticonvulsantdrugsshould

notbediscontinuedinpatientsinwhomthedrugisadministeredtopreventmajorseizuresbecauseofthestrong

possibilityofprecipitatingstatusepilepticuswithattendanthypoxiaandthreattolife.

Inindividualcaseswheretheseverityandfrequencyoftheseizuredisorderaresuchthattheremovalofmedication

doesnotposeaseriousthreattothepatient,discontinuationofthedrugmaybeconsideredpriortoandduring

pregnancyalthoughitcannotbesaidwithanyconfidencethatevenminorseizuresdonotposesomehazardtothe

developingembryoorfoetus.

Anticonvulsantsincludingphenytoinmayproducecongenitalabnormalitiesintheoffspringofasmallnumberof

epilepticpatients.Theexactroleofdrugtherapyintheseabnormalitiesisunclearandgeneticfactors,insomestudies,

havealsobeenshowntobeimportant.Epanutinshouldonlybeusedduringpregnancy,especiallyearlypregnancy,if

inthejudgementofthephysicianthepotentialbenefitsclearlyoutweightherisk.

Inadditiontothereportsofincreasedincidenceofcongenitalmalformations,suchascleftlip/palateandheart

malformationsinchildrenofwomenreceivingphenytoinandotherantiepilepticdrugs,therehavemorerecentlybeen

reportsofafoetalhydantoinsyndrome.

Thisconsistsofprenatalgrowthdeficiency,microencephalyandmentaldeficiencyinchildrenborntomotherswho

havereceivedphenytoin,barbiturates,alcohol,ortrimethadione.

However,thesefeaturesareallinterrelatedandarefrequentlyassociatedwithintrauterinegrowthretardationfrom

othercauses.

Therehavebeenisolatedreportsofmalignancies,includingneuroblastoma,inchildrenwhosemothersreceived

phenytoinduringpregnancy.

Anincreaseinseizurefrequencyduringpregnancyoccursinaproportionofpatients,andthismaybeduetoaltered

phenytoinabsorptionormetabolism.Periodicmeasurementofserumphenytoinlevelsisparticularlyvaluableinthe

managementofapregnantepilepticpatientasaguidetoanappropriateadjustmentofdosage.However,postpartum

restorationoftheoriginaldosagewillprobablybeindicated.

Neonatalcoagulationdefectshavebeenreportedwithinthefirst24hoursinbabiesborntoepilepticmothersreceiving

phenytoin.VitaminKhasbeenshowntopreventorcorrectthisdefectandmaybegiventothemotherbeforedelivery

andtotheneonateafterbirth.

Infantbreastfeedingisnotrecommendedforwomentakingphenytoinbecausephenytoinappearstobesecretedinlow

concentrationsinhumanmilk.

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbeadvisednottodriveacaroroperatepotentiallydangerousmachineryuntilitisknownthatthis

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4.8Undesirableeffects

Immunesystemreactions:Anaphylactoidreactionandanaphylaxis

CentralNervousSystem

Themostcommonmanifestationsencounteredwithphenytointherapyarereferabletothissystemandareusually

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

paraesthesia,somnolence,drowsinessandvertigo.

Dizziness,insomnia,transient,nervousness,motortwitching,tasteperversionandheadacheshavealsobeen

observed.Therehavealsobeenrarereportsofphenytoininduceddyskinesias,includingchorea,dystonia,tremor

andasterixis,similartothoseinducedbyphenothiazineandotherneurolepticdrugs.

Thereareoccasionalreportsofirreversiblecerebellardysfunctionassociatedwithseverephenytoinoverdosage.A

predominantlysensoryperipheralpolyneuropathyhasbeenobservedinpatientsreceivinglong-termphenytoin

therapy.

Gastrointestinal

Nausea,vomitingandconstipation,toxichepatitis,andliverdamage.

Dermatological

Dermatologicalmanifestationssometimesaccompaniedbyfeverhaveincludedscarlatiniformormorbilliform

rashes.Amorbilliformrashisthemostcommon;dermatitisisseenmorerarely.Othermoreseriousandrareforms

haveincludedbullous,exfoliativeorpurpuricdermatitis,lupuserythematosus,Stevens-Johnsonsyndromeandtoxic

epidermalnecrolysis(seeSection4.4).

ConnectiveTissue

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

DiseaseandDupuytren'scontracturemayoccurrarely.

Haemopoietic

Haemopoieticcomplications,somefatal,haveoccasionallybeenreportedinassociationwithadministrationof

phenytoin.Thesehaveincludedthrombocytopenia,leucopenia,granulocytopenia,agranulocytosis,pancytopenia

withorwithoutbonemarrowsuppression,andaplasticanaemia.Whilemacrocytosisandmegaloblasticanaemia

haveoccurred,theseconditionsusuallyrespondtofolicacidtherapy.

Therehavebeenanumberofreportssuggestingarelationshipbetweenphenytoinandthedevelopmentof

lymphadenopathy(localandgeneralised)includingbenignlymphnodehyperplasia,pseudolymphoma,lymphoma,

andHodgkin'sDisease.Althoughacauseandeffectrelationshiphasnotbeenestablished,theoccurrenceof

lymphadenopathyindicatestheneedtodifferentiatesuchaconditionfromothertypesoflymphnodepathology.

Lymphnodeinvolvementmayoccurwithorwithoutsymptomsandsignsresemblingserumsickness,eg.fever,rash

andliverinvolvement.

Inallcasesoflymphadenopathy,follow-upobservationforanextendedperiodisindicatedandeveryeffortshould

bemadetoachieveseizurecontrolusingalternativeantiepilepticdrugs.

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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)useofphenytoinbypatientswith

chronicepilepsy.Osteoporosisandotherdisordersofbonemetabolismsuchashypocalcemia,hypophophatemiaand

decreasedlevelsofVitaminDmetaboliteshavealsobeenreported.

4.9Overdose

Thelethaldoseinchildrenisnotknown.Themeanlethaldoseforadultsisestimatedtobe2to5g.Theinitial

symptomsarenystagmus,ataxiaanddysarthria.Thepatientthenbecomescomatose,thepupilsareunresponsiveand

hypotensionoccursfollowedbyrespiratorydepressionandapnoea.Deathisduetorespiratoryandcirculatory

depression.

Therearemarkedvariationsamongindividualswithrespecttophenytoinserumlevelswheretoxicitymayoccur.

Nystagmusonlateralgazeusuallyappearsat20mg/l,andataxiaat30mg/l,dysarthriaandlethargyappearwhenthe

serumconcentrationisgreaterthan40mg/l,butaconcentrationashighas50mg/lhasbeenreportedwithout

evidenceoftoxicity.

Asmuchas25timestherapeuticdosehasbeentakentoresultinserumconcentrationover100mg/l(400

micromoles/l)withcompleterecovery.

Treatment

Treatmentisnon-specificsincethereisnoknownantidote.Ifingestedwithintheprevious4hoursthestomach

shouldbeemptied.Ifthegagreflexisabsent,theairwayshouldbesupported.Oxygenandassistedventilationmay

benecessaryforcentralnervoussystem,respiratoryandcardiovasculardepression.Haemodialysiscanbe

consideredsincephenytoinisnotcompletelyboundtoplasmaproteins.Totalexchangetransfusionhasbeenutilised

inthetreatmentofsevereintoxicationinchildren.

InacuteoverdosagethepossibilityofthepresenceofotherCNSdepressants,includingalcohol,shouldbebornein

mind.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Phenytoiniseffectiveinvariousanimalmodelsofgeneralisedconvulsivedisorders,reasonablyeffectiveinmodelsof

partialseizuresbutrelativelyineffectiveinmodelsofmyoclonicseizures.

Itappearstostabiliseratherthanraisetheseizurethresholdandpreventsspreadofseizureactivityratherthanabolish

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Themechanismbywhichphenytoinexertsitsanticonvulsantactionhasnotbeenfullyelucidatedhowever,possible

contributoryeffectsinclude:

5.2Pharmacokineticproperties

Phenytoinisabsorbedfromthesmallintestineafteroraladministration.Variousformulationfactorsmayaffectthe

bioavailabilityofphenytoin,however,non-lineartechniqueshaveestimatedabsorptiontobeessentiallycomplete.

AfterabsorptionitisdistributedintobodyfluidincludingCSF.Itsvolumeofdistributionhasbeenestimatedtobe

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

Theplasmahalf-lifeofphenytoininmanaverages22hourswitharangeof7to42hours.Steadystatetherapeutic

druglevelsareachievedatleast7to10daysafterinitiationoftherapy.

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

Core

Lactosemonohydrate

Magnesiumstearate

Sodiumlaurilsulfate

Shell

Gelatin

Titaniumdioxide(E171)

Erythrosine(E127)

Quinolineyellow(E104)

Printingink

Shellac

Blackironoxide(E172)

Non-synapticeffectstoreducesodiumconductance,enhanceactivesodiumextrusion,

blockrepetitivefiringandreducepost-tetanicpotentiation.

Post-synapticactiontoenhancegaba-mediatedinhibitionandreduceexcitatory

synaptictransmission.

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6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackageinordertoprotectfromlight

6.5Natureandcontentsofcontainer

Whiteplasticcontainerwithwhiteplasticcap,containing84capsules

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare,

Unit4,BradfieldRoad

Ruislip

Middlesex

HA40NU

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/147/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15thApril2011

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