EPANUTIN

Main information

  • Trade name:
  • EPANUTIN Capsules Hard 300 Milligram
  • Dosage:
  • 300 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPANUTIN Capsules Hard 300 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/051/002
  • Authorization date:
  • 16-09-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epanutin300mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachcapsulecontainsPhenytoinSodium300mg

Eachcapsulealsocontainslactosemonohydrate

Forfulllistofexcipients,seeSection6.1

3PHARMACEUTICALFORM

Capsules,hard

ProductimportedfromtheUK:

AwhitepowderinaNo1hardgelatincapsulewithawhiteopaquebodyandgreencap,radiallyprinted'EPANUTIN

300'.

4CLINICALPARTICULARS

4.1TherapeuticIndications

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

ofthese,andthepreventionandtreatmentofseizuresoccurringduringorfollowingneurosurgeryand/orseverehead

injury.Epanutinhasalsobeenemployedinthetreatmentoftrigeminalneuralgiabutitshouldonlybeusedassecond

linetherapyifcarbamazepineisineffectiveorpatientsareintoleranttocarbamazepine.

4.2Posologyandmethodofadministration

Fororaladministrationonly.

Dosage

Dosageshouldbeindividualisedastheremaybewideinterpatientvariabilityinphenytoinserumlevelswithequivalent

dosage.Epanutinshouldbeintroducedinsmalldosageswithgradualincrementsuntilcontrolisachievedoruntiltoxic

effectsappear.Insomecasesserumleveldeterminationsmaybenecessaryforoptimaldosageadjustments-the

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

becontrolledwithlowerserumlevelsofphenytoin.Withrecommendeddosageaperiodofseventotendaysmaybe

requiredtoachievesteadystateserumlevelswithEpanutinandchangesindosageshouldnotbecarriedoutatintervals

shorterthanseventotendays.

Maintenanceoftreatmentshouldbethelowestdoseofanticonvulsantconsistentwithcontrolofseizures.

EpanutinCapsules,SuspensionandInfatabs

EpanutinCapsulescontainphenytoinsodiumwhereasEpanutinSuspensionandEpanutinInfatabscontainphenytoin.

Although100mgofphenytoinsodiumisequivalentto92mgofphenytoinonamolecularweightbasis,thesemolecular

equivalentsarenotnecessarilybiologicallyequivalent.Physiciansshouldthereforeexercisecareinthosesituations

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Adults

Initially3to4mg/kg/daywithsubsequentdosageadjustmentifnecessary.Formostadultsasatisfactorymaintenance

dosewillbe200to500mgdailyinsingleordivideddoses.Exceptionally,adailydoseoutsidethisrangemaybe

indicated.Dosageshouldnormallybeadjustedaccordingtoserumlevelswhereassayfacilitiesexist.

Elderly

Elderly(over65years):AswithadultsthedosageofEpanutinshouldbetitratedtothepatient'sindividual

requirementsusingthesameguidelines.Aselderlypatientstendtoreceivemultipledrugtherapies,thepossibilityof

druginteractionsshouldbeborneinmind.

InfantsandChildren

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

recommendeddailymaintenancedosageisusually4-8mg/kg.

Neonates

Theabsorptionofphenytoinfollowingoraladministrationinneonatesisunpredictable.Furthermore,themetabolism

ofphenytoinmaybedepressed.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

together,combineddrugtherapyisneeded.

Phenytoinmayaffectglucosemetabolismandinhibitinsulinrelease.Hyperglycaemiahasbeenreportedinassociation

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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,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.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

measuredatleastonceevery6months,andfolicacidsupplementsgivenifnecessary.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactosedeficiencyorglucose-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.

SerumlevelsofphenytoincanbereducedbyconcomitantuseoftheherbalpreparationscontainingSt.John’swort

(Hypericumperforatum).ThisisduetoinductionofdrugmetabolisingenzymesbySt.John’swort.Herbal

preparationscontainingSt.John’swortshouldthereforenotbecombinedwithphenytoin.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,tricyclicantidepressantsandphenothiazinesmayprecipitate

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.

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Drug/LaboratoryTestInteractions

Phenytoinmaycauseaslightdecreaseinserumlevelsoftotalandfreethyroxine,possiblyasaresultofenhanced

peripheralmetabolism.Thesechangesdonotleadtoclinicalhypothyroidismanddonotaffectthelevelsofcirculating

TSH.Thelattercanthereforebeusedfordiagnosinghypothyroidisminthepatientonphenytoin.Phenytoindoesnot

interferewithuptakeandsuppressiontestsusedinthediagnosisofhypothyroidism.Itmay,however,producelower

thannormalvaluesfordexamethasoneormetapyronetests.Phenytoinmaycauseraisedserumlevelsofglucose,

alkalinephosphatase,andgammaglutamyltranspeptidaseandloweredserumlevelsofcalciumandfolicacid.Itis

recommendedthatserumfolateconcentrationsbemeasuredatleastonceevery6months,andfolicacidsupplements

givenifnecessary.Phenytoinmayaffectbloodsugarmetabolismtests.

4.6Fertility,pregnancyandlactation

Thereareintrinsicmethodologicalproblemsinobtainingadequatedataondrugteratogenicityinhumans.Genetic

factorsortheepilepticconditionitselfmaybemoreimportantthandrugtherapyinleadingtobirthdefects.Thegreat

majorityofmothersonanticonvulsantmedicationdelivernormalinfants.

Itisimportanttonotethatanticonvulsantdrugsshouldnotbediscontinuedinpatientsinwhomthedrugis

administeredtopreventmajorseizuresbecauseofthestrongpossibilityofprecipitatingstatusepilepticuswith

attendanthypoxiaandthreattolife.

Inindividualcaseswheretheseverityandfrequencyoftheseizuredisorderaresuchthattheremovalofmedication

doesnotposeaseriousthreattothepatient,discontinuationofthedrugmaybeconsideredpriortoandduring

pregnancyalthoughitcannotbesaidwithanyconfidencethatevenminorseizuresdonotposesomehazardtothe

developingembryoorfoetus.

Anticonvulsantsincludingphenytoinmayproducecongenitalabnormalitiesintheoffspringofasmallnumberof

epilepticpatients.Theexactroleofdrugtherapyintheseabnormalitiesisunclearandgeneticfactors,insomestudies,

havealsobeenshowntobeimportant.Epanutinshouldonlybeusedduringpregnancy,especiallyearlypregnancy,if

inthejudgementofthephysicianthepotentialbenefitsclearlyoutweightherisk.

Inadditiontothereportsofincreasedincidenceofcongenitalmalformations,suchascleftlip/palateandheart

malformationsinchildrenofwomenreceivingphenytoinandotherantiepilepticdrugs,therehavemorerecentlybeen

reportsofafoetalhydantoinsyndrome.Thisconsistsofprenatalgrowthdeficiency,microencephalyandmental

deficiencyinchildrenborntomotherswhohavereceivedphenytoin,barbiturates,alcohol,ortrimethadione.However,

thesefeaturesareallinterrelatedandarefrequentlyassociatedwithintrauterinegrowthretardationfromothercauses.

Therehavebeenisolatedreportsofmalignancies,includingneuroblastoma,inchildrenwhosemothersreceived

phenytoinduringpregnancy.

Anincreaseinseizurefrequencyduringpregnancyoccursinaproportionofpatients,andthismaybeduetoaltered

phenytoinabsorptionormetabolism.Periodicmeasurementofserumphenytoinlevelsisparticularlyvaluableinthe

managementofapregnantepilepticpatientasaguidetoanappropriateadjustmentofdosage.However,postpartum

restorationoftheoriginaldosagewillprobablybeindicated.

Neonatalcoagulationdefectshavebeenreportedwithinthefirst24hoursinbabiesborntoepilepticmothersreceiving

phenytoin.VitaminKhasbeenshowntopreventorcorrectthisdefectandmaybegiventothemotherbeforedelivery

andtotheneonateafterbirth.

Infantbreast-feedingisnotrecommendedforwomentakingphenytoinbecausephenytoinappearstobesecretedinlow

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,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

madetoachieveseizurecontrolusingalternativeantiepilepticdrugs.

Frequentbloodcountsshouldbecarriedoutduringtreatmentwithphenytoin.

ImmuneSystem

Hypersensitivitysyndromehasbeenreportedandmayinrarecasesbefatal(thesyndromemayinclude,butisnot

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

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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

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

Preclinicalsafetydatadonotaddanythingoffurthersignificancetotheprescriber.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Magnesiumstearate

Silica

Gelatin

PatentblueV(E131)

Quinolineyellow(E104)

Titaniumdioxide(E171)

Sodiumlaurilsulfate

Printingink:

Shellac

Blackironoxide(E172)

Non-synapticeffectstoreducesodiumconductance,enhanceactivesodiumextrusion,

blockrepetitivefiringandreducepost-tetanicpotentiation.

Post-synapticactiontoenhancegaba-mediatedinhibitionandreduceexcitatory

synaptictransmission.

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblistersorouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25˚C.Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

PVC/PVdCblisterpackasanoverlabelledcartonof28capsules

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton

Oldham

Lancashire

OL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/51/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16thSeptember2011.

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