EFLAVEX 4 MG TABLETS

Main information

  • Trade name:
  • EFLAVEX 4 MG TABLETS
  • Dosage:
  • 4 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EFLAVEX 4 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0436/044/003
  • Authorization date:
  • 29-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0436/044/003

CaseNo:2036252

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NortonWaterfordLimited

T/AIVAXPharmaceuticalsIreland,IDAIndustrialPark,Waterford,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Eflavex4mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom09/07/2008until28/02/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Eflavex4mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains4mgcabergoline.

Excipient:lactose301.2mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Thetabletcanbedividedintoequalhalves.

White,oval,biconvextabletswithscoresonbothsides.Onesideisdebossedwith‘CBG’and‘4’oneithersideofthe

score.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofParkinson’sdisease

Iftreatmentwithadopamineagonistisbeingconsidered,eflavexisindicatedassecondlinetherapyinpatientswhoare

intolerantorfailtreatmentwithanon-ergotcompound,asmonotherapy,orasadjunctivetreatmenttolevodopaplus

dopa-decarboxylaseinhibitor,inthemanagementofthesignsandsymptomsofParkinson’sdisease.

Treatmentshouldbeinitiatedunderspecialistsupervision.Thebenefitofcontinuedtreatmentshouldberegularly

reassessed,takingintoaccounttheriskoffibroticreactionsandvalvulopathy(seesection4.3,4.4and4.8).

4.2Posologyandmethodofadministration

Eflavexistobeadministeredbytheoralroute.Inordertoreducetheriskofgastrointestinalundesirableeffectsitis

recommendedthateflavexistakenwithmealsforalltherapeuticindications.

Adultsandelderlypatients:

Asexpectedfordopamineagonists,doseresponseforbothefficacyandundesirableeffectsappearstobelinkedto

individualsensitivity.Optimizationofdoseshouldbeobtainedthroughslowinitialdosetitration,fromstartingdoses

of0.5mgeflavex(denovopatients)and1mgeflavex(patientsonLdopa)daily.Thedosageofconcurrentlevodopa

maybegraduallydecreased,whilethedosageofeflavexisincreased,untiltheoptimumbalanceisdetermined.Inview

ofthelonghalf-lifeofthecompound,incrementsofthedailydoseof0.5-1mgeflavexshouldbedoneatweekly

(initialweeks)orbi-weeklyintervals,uptooptimaldoses.

Therecommendedtherapeuticdosageis2to6mgeflavex/dayasadjuvanttherapytolevodopa/carbidopa.Eflavex

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Useinchildrenandadolescents:

ThesafetyandefficacyofeflavexhasnotbeeninvestigatedinchildrenoradolescentsasParkinson’sdiseasedoesnot

affectthispopulation.

Useinpatientswithhepaticorrenaldysfunction

Forpatientswithseverehepaticdysfunctionorendstagerenalfailureseesection4.3and4.4.

4.3Contraindications

Hypersensitivitytoeflavex,otherergotalkaloidsortoanyoftheexcipients.

Pre-eclampsia,eclampsia

Uncontrolledhypertension.

Historyofpulmonary,pericardialandretroperitonealfibroticdisorders.

Anatomicalevidenceofcardiacvalvulopathyofanyvalve(e.g.,echocardiogramshowingvalveleafletthickening,

valverestriction,valvemixedrestriction-stenosis).

4.4Specialwarningsandprecautionsforuse

General

Theassessmentofsafetyandefficacyofeflavexislimitedinpatientswithrenalandhepaticdisease.Aswithother

ergotalkaloids,eflavexshouldbegivenwithcautiontosubjectswithcardiovasculardisease,hypotension,Raynaud's

syndrome,pepticulcerorgastrointestinalbleeding.Theeffectsofalcoholonoveralltolerabilityofeflavexare

currentlyunknown.

Eflavexshouldbegivenwithcautiontopatientswithahistoryofpsychoticdisorders,ahistoryofseriousorpsychotic

mentaldiseaseorwherethereisariskofpost-partumpsychosis.

FibrosisandCardiacValvulopathy

Fibroticandserosalinflammatorydisorderssuchaspleuritis,pleuraleffusion,pleuralfibrosis,pulmonaryfibrosis,

pericarditis,pericardialeffusion,cardiacvalvulopathyinvolvingoneormorevalves(aortic,mitralandtricuspid)or

retroperitonealfibrosishaveoccurredafterprolongedusageofeflavex.Insomecases,symptomsormanifestationsof

cardiacvalvulopathyimprovedafterdiscontinuationofeflavex.

Erythrocytesedimentationrate(ESR)hasbeenfoundtobeabnormallyincreasedinassociationwithpleural

effusion/fibrosis.Chestx-rayexaminationisrecommendedincasesofunexplainedESRincreasestoabnormalvalues.

Serumcreatinemeasurementscanalsobeusedtohelpinthediagnosisoffibroticdisorder.

Beforeinitiatingtreatment:

Allpatientsshouldundergoacardiovascularevaluation,includingechocardiogram,toassessthepotentialpresenceof

asymptomaticvalvulardisease.ItmaybeappropriatetoperformbaselineinvestigationsofESRorotherinflammatory

markers,lungfunction/chestx-rayandrenalfunctionpriortoinitiationoftherapy.Iffibroticvalvulardiseaseis

detected,thepatientshouldnotbetreatedwitheflavex.(SeeSection4.3).

Valvulopathywasassociatedwithcumulativedoses.

Duringtreatment:

Fibroticdisorderscanhaveaninsidiousonsetandpatientsshouldberegularlymonitoredforpossiblemanifestationsof

progressivefibrosis.Thereforeduringtreatment,attentionshouldbepaidtothesignsandsymptomsof:

Pleuropulmonarydisease,suchasdyspnoea,shortnessofbreath,persistentcough,orchestpain.

Renalinsufficiencyorureteral/abdominalvascularobstructionthatmayoccurwithpainintheloin/flank,andlower

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Cardiacfailure,ascasesofpericardialfibrosishaveoftenmanifestedascardiacfailure;constrictivepericarditis

shouldbeexcludedifsuchsymptomsappear.

Cardiacfailure,ascasesofvalvularfibrosishaveoftenmanifestedascardiacfailure;valvularfibrosisshouldbe

excludedifsuchsymptomsappear.

Clinicaldiagnosticmonitoringfordevelopmentofvalvulardiseaseorfibrosis,asappropriate,isrecommended.

Followingtreatmentinitiation,thefirstechocardiogramshouldoccurwithin3-6months,thereafter,thefrequencyof

echocardiographicmonitoringshouldbedeterminedbyappropriateindividualclinicalassessmentwithparticular

emphasisontheabove-mentionedsignsandsymptoms,butshouldoccurataleastevery6to12months.

Eflavexshouldbediscontinuedifanechocardiogramrevealsneworworsenedvalvularregurgitation,valvular

restrictionorvalveleafletthickening.(SeeSection4.3)Theneedforotherclinicalmonitoring(e.g.,physical

examination,carefulcardiacauscultation,X-ray,echocardiogram,CTscan)shouldbedeterminedonanindividual

basis.

Hypotension:

Symptomatichypotensioncanoccurwithin6hoursfollowingadministrationofeflavex:particularattentionshouldbe

paidwhenadministeringeflavexconcomitantlywithothermedicinalproductknowntolowerbloodpressure.Because

ofitseliminationhalf-lifehypotensiveeffectsmaypersistforafewdaysaftercessationoftherapy.Monitoringof

treatmentwithregularchecksofbloodpressureisrecommendedinthefirst3-4daysafterinitiationoftreatment.

CNS:Eflavexhasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,particularlyinpatientswith

Parkinson'sdisease.Suddenonsetofsleepduringactivities,insomecaseswithoutawarenessorwarningsigns,has

beenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhiledrivingor

operatingmachinesduringtreatmentwitheflavex.Patientswhohaveexperiencedsomnolenceand/oranepisodeof

suddensleeponsetmustrefrainfromdrivingoroperatingmachines.Furthermoreareductionofdosageortermination

oftherapymaybeconsidered.

RenalInsufficiency:Nooveralldifferencesinthepharmacokineticsofeflavexwereobservedinmoderatetosevere

renaldisease.Thepharmacokineticsofeflavexhasnotbeenstudiedinpatientshavingend-stagerenalfailure,orin

patientsonhaemodialysis;thesepatientsshouldbetreatedwithcaution.

HepaticInsufficiency:Eflavexpharmacokineticsinpatientswithmildtomoderatedysfunction(Child-Pughscore<10)

weresimilartothosedeterminedinpreviousstudiesinsubjectswithnormalhepaticfunction.However,patientswith

themostseveredysfunction(Child-Pughscore>10)showedincreasedAUCvalues(>200%).Thesepatientsshouldbe

dosedwithcaution,anditisrecommendedthatdailydoseshouldbelimitedtonomorethan1mg.

Other

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson’sdisease,includingeflavex.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusenotrecommended

Elevatedplasmalevelsofbromocriptinehavebeenobservedincombinationwithmacrolideantibiotics(suchas

erythromycin).Effectsofmacrolideantibioticsoneflavex’splasmalevelswhenadministeredsimultaneouslyhavenot

beenstudied.Thecombinationshouldbeavoided,asitmayresultinelevatedeflavexplasmalevels.

Eflavexactsthroughdirectstimulationofdopaminereceptors.Consequently,itshouldnotbecombinedwithmedicinal

productswithadopamineantagonisticeffect(suchasphenothiazines,butyrophenones,thioxanthenes,

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Noinformationisavailableaboutpossibleinteractionsbetweeneflavexandotherergotalkaloids.Therefore,long-term

treatmentwitheflavexisnotadvisedincombinationwiththesemedicinalproducts.

Precautions

Interactionswithothermedicinalproductsthatreducebloodpressureshouldbetakenintoconsideration.

NopharmacokineticinteractionswithL-dopaorselegilinehavebeenobservedinstudiesofpatientswithParkinson’s

disease.Pharmacokineticinteractionswithothermedicinalproductscannotbepredictedbasedonavailableinformation

aboutthemetabolismofeflavex.

4.6Pregnancyandlactation

Pregnancy

Beforeeflavexadministration,pregnancyshouldbeexcludedandaftertreatmentshouldbepreventedforatleastone

month.

Eflavexhasbeenshowntocrosstheplacentainrats.Itisnotknownwhetherthisoccursinhumans.Dataonalimited

numberofpregnancies(n=100),generallytakenduringthefirst8weeksafterconception,donotindicateeflavextobe

associatedwithanincreasedriskofabortion,prematuredelivery,multiplepregnancyorcongenitalabnormalities.To

date,nootherrelevantepidemiologicaldataareavailable.Animalstudiesindicatenodirectorindirectharmfuleffects

withrespecttopregnancy,embryonal/foetaldevelopment,parturitionorpost-nataldevelopment.

Becauseofthelimitedexperienceoftheuseofeflavexinpregnancy,eflavexshouldbewithdrawnbeforeaplanned

pregnancy.Ifthepatientbecomespregnantduringtreatment,eflavexshallbeimmediatelywithdrawn.During

pregnancy,thesepatientsmustbecarefullymonitoredforanypregnancy-inducedpituitaryenlargement.

Eflavexshouldonlybeusedduringpregnancyifclearlyindicated.

Eflavexrestoresovulationandfertilityinwomenwithhyperprolactinaemichypogonadism:sincepregnancymight

occurpriortoreinitiationofmenses,pregnancytestingisrecommendedasappropriateduringtheamenorrhoeicperiod

and,oncemensesarereinitiated,everytimeamenstrualperiodisdelayedbymorethanthreedays.Womennotseeking

pregnancyshouldbeadvisedtouseeffectivenon-hormonalcontraceptionduringtreatmentandaftereflavex

withdrawal.Becauseoflimitedexperienceonthesafetyoffoetalexposuretoeflavex,itisadvisablethatwomen

seekingpregnancyconceiveatleastonemonthaftereflavexdiscontinuationgiventhatovulatorycyclespersistinsome

patientsfor6monthsafterwithdrawal.Shouldpregnancyoccurduringtreatment,eflavexistobediscontinued.Asa

precautionarymeasure,womenwhobecomepregnantshouldbemonitoredtodetectsignsofpituitaryenlargement

sinceexpansionofpre-existingpituitarytumoursmayoccurduringgestation.

Contraceptionshouldbecontinuedforatleast4weeksafterstoppingeflavex.

Lactation

Eflavexshouldnotbeadministeredtomotherswhoelecttobreastfeedtheirinfantssinceitpreventslactation.No

informationisavailableontheexcretionofactivesubstanceinmaternalmilkbutinratseflavexand/oritsmetabolites

areexcretedinthemilk.

Lactationshouldbeavoidedwhentakingeflavex.

4.7Effectsonabilitytodriveandusemachines

Eflavexreducesbloodpressure,whichmayimpairthereactionsofcertainpatients.Thisshouldbetakenintoaccount

insituationsrequiringintenseawareness,suchaswhendrivingacaroroperatingmachinery.

Patientstreatedwitheflavexandpresentingwithsomnolenceand/orsuddensleepepisodesmustbeinformedtorefrain

fromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersatriskofseriousinjuryor

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4.8Undesirableeffects

About1070parkinsonianpatientshavereceivedeflavexasadjuvanttherapytoL-dopainclinicalstudies;ofthese74%

hadatleastoneadverseevent,mainlyofmildtomoderateseverityandtransientinnature,andrequiring

discontinuationinasmallproportionofcases.

Nervoussystemdisorders:

Inthemajorityofcases(51%),eventswererelatedtothenervoussystem:mostfrequentlyreportedeventswere

dyskinesia,dizziness,hyperkinesia,hallucinationsorconfusion.

Gastrointestinaldisorders:

Thegastrointestinalsystemwasinvolvedin33%ofcases:eventsmostfrequentlyreportedwerenausea,vomiting,

dyspepsiaandgastritis.

Cardiacdisorders:

Thecardiovascularsystemwasinvolvedin27%ofcases,mostfrequentlyreportedeventbeinghypotension.

Respiratory,thoracicandmediastinaldisorders:

Therespiratorysystemwasinvolvedin13%ofcases,symptomaticpleuraleffusion/fibrosisbeingreportedwitha

frequency<2%.

Therehavebeenreportsoffibroticandserosalinflammatoryconditions,suchaspleuritis,pleuraleffusion,pleural

fibrosis,pulmonaryfibrosis,pericarditis,pericardialeffusion,cardiacvalvulopathyandretroperitonealfibrosis,in

patientstakingeflavex(see‘Specialwarningsandspecialprecautionsforuse’).Theincidenceofvalvulopathywith

eflavexisnotknown,howeverbasedonrecentstudiesoftheprevalenceofvalvularregurgitation(themostsensitive

echocardiogaphicmarkerforrestrictivevalvulopathy),theprevalenceofregurgitation(virtuallyallcases

asymptomatic)potentiallyattributabletoeflavexmaybeintherangeof20%orgreater.

Thereislimitedinformationavailableonthereversibilityofthesereactions.

Otheradverseeventsexpectedforthepharmacologicalclass,inviewofthevasoconstrictiveproperties,includeangina

(reportedinabout1%ofthepatientsoneflavex)anderythromelalgia(observedin0.4%ofthepatients).Similarly

expectedforthepharmacologicalclass,peripheraloedemaoccurredin6%ofpatients.

Gastricupsetwasmorefrequentinfemalethaninmalepatients,whileCNSeventsweremorefrequentintheelderly.

Abloodpressuredecreaseofclinicalrelevancewasobservedmainlyonstandinginaminorityofpatients.Theeffect

wasmainlyevidentinthefirstweeksoftherapy.NeithermodificationofheartratenorconsistentchangesofECG

tracingwereobservedduringeflavextreatment.

Alterationsinstandardlaboratorytestsareuncommonduringlongtermtherapywitheflavex.Inclinicalstudies,

increasesoftriglyceridesgreaterthan30%abovetheupperlimitofthelaboratoryreferencerangewereobservedin

6.8%oftheeflavex-treatedpatientswhohadvalueswithinthenormalrangeatbaseline.Inmostcasestheincreases

weretransient.Noclearindicationsofincreasesovertimeorsignificantshiftsfromnormaltoabnormalvalueswere

observedintheoverallgroupofpatientstreatedwitheflavex.Aclinicallyrelevantdecreaseinhaemoglobin,

haematocritand/orredbloodcellcount>15%Vsbaseline)wasobservedatleastoncein6.8%ofclinicalstudypatients

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Post-marketingSurveillance:

Eflavexisassociatedwithsomnolenceandhasbeenassociateduncommonlywithexcessivedaytimesomnolenceand

suddensleeponsetepisodes.

PatientstreatedwithdopamineagonistsfortreatmentofParkinson’sdisease,includingeflavex,especiallyathigh

doses,havebeenreportedasshowingpathologicalgambling,increasedlibidoandhypersexuality,generallyreversible

uponreductionofthedoseortreatmentdiscontinuation.

Thefollowingeventshavebeenreportedinassociationwitheflavex:

Valvulopathyandfibrosis.(Seesection4.4)–Fibrosis/Valvulopathy).

Hallucinations

Other:

Adverseeventshavebeenreportedwithlowerdosesofeflavex(0.25–2mgperweek)thatarenotlistedabove

Disordersinthecentraland

peripheralnervoussystem

Verycommon(1/10)

Common(1/100and<1/10)

Rare(1/10,000and<1/1000) Dyskinesia,dizziness,hyperkinesia.

Drowsiness,Sleepdisorders,hallucinations,confusion

Episodeswherethepatientsuddenlyfallsasleep

Cardiacdisorders

Verycommon(1/10)

Common(1/100and<1/10)

Uncommon(1/1000and<1/100) Orthostatichypotension

Angina

Erythromelalgia

Disordersoftherespiratorytract,

thoraxandmediastinum

Common(1/100and<1/10) Symptomaticpleuralexudate/pulmonaryfibrosis

Gastrointestinaldisorders

Verycommon(1/10)

Common(1/100and<1/10) Nausea

Vomiting,dyspepsia,gastritis,constipation.

Generalsymptomsanddisorders

atthesiteofapplication

Common(1/100and<1/10) Peripheraloedemas

Examinations

Common(1/100and<1/10) Afallinhaemoglobinandhaematocritvalues,fallinthe

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Common(>1/100,<1/10)

Nervoussystemdisorders:Depression,headache,fatigue,paresthesia,somnolence.

Cardiacdisorders:Palpitations

Gastrointestinaldisorders:Constipation

Skinandsubcutaneoustissuedisorders:Facialredness

Uncommon(>1/1000,<1/100)

Eyedisorders:Hemianopsia

Vasculardisorders:Nosebleeding

Rare(>1/10000,<1/1000)

Vasculardisorders:Fainting

Musculoskeletal,connectivetissueandbonedisorders:Crampinfingersandcalves

4.9Overdose

Thereisnoclinicalexperienceofoverdosing,butobservationsfromanimalexperimentssuggestthatsymptoms

resultingfromoverstimulationofdopaminereceptorscanbeexpected,suchasnausea,vomiting,reducedblood

pressure,confusion/psychosisorhallucinations.Whereindicated,measuresmustbetakentorestorebloodpressure.In

addition,withpronouncedsymptomsfromtheCNS(hallucinations),administrationofadopamineantagonistcanbe

necessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Dopamineagonist.

ATCCode:N04BC06

Eflavexisasyntheticergotalkaloidandanergolinederivatewithlong-actingdopamineagonistandprolactin-

inhibitingproperties.AcentraldopaminergiceffectviaD2-receptorstimulationisachievedthroughhigherdosesthan

dosesthatreducethelevelsofserumprolactin.

Controlledclinicalstudieshavedemonstratedthateflavexiseffectiveatanaveragedoseof4mg/dayfollowingtitration

(upto5-6mgeflavex/dayinthedifferentstudies).Eflavexreducesdailyfluctuationsinthemotorfunctioninpatients

withParkinson’sdiseasethatarebeingtreatedwithlevodopa/carbidopa.Innewlydiagnosedpatients,eflavex

administeredasmonotherapyhasbeenshowntoproducesomewhatlessfrequentclinicalimprovementcomparedwith

levodopa/carbidopa.

Withregardtotheendocrineeffectsofeflavexnotrelatedtotheantiprolactinaemiceffect,availabledatafromhumans

confirmtheexperimentalfindingsinanimalsindicatingthatthetestcompoundisendowedwithaveryselectiveaction

withnoeffectonbasalsecretionofotherpituitaryhormonesorcortisol.

Thepharmacodynamicactionsofeflavexnotcorrelatedwiththetherapeuticeffectonlyrelatetobloodpressure

decrease.Themaximalhypotensiveeffectofeflavexassingledoseusuallyoccursduringthefirst6hoursafteractive

substanceintakeandisdose-dependentbothintermsofmaximaldecreaseandfrequency.

5.2Pharmacokineticproperties

Absorption

Afteroraladministrationeflavexisrapidlyabsorbedfromthegastrointestinaltractasthepeakplasmaconcentrationis

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Fooddoesnotappeartoaffectabsorptionanddispositionofeflavex.

Distribution

“In-vitro”experimentsshowedthateflavexatconcentrationsof0.1–10ng/mlis41-42%boundtoplasmaproteins.

Biotransformation

Inurine,themainmetaboliteidentifiedis6-allyl-8ß-carboxy-ergoline,whichaccountsfor4-6%ofthedose.Three

additionalmetabolitesareidentifiedinurine,whichaccountoverallforlessthan3%ofthedose.Themetaboliteshave

beenfoundtobemuchlesspotentthaneflavexininhibitingprolactinsecretion“in-vitro”.

Elimination

Theeliminationhalf-lifeofeflavex,islong;(63-68hoursinhealthyvolunteersand79-115hoursin

hyperprolactinaemicpatients.

Onthebasisoftheeliminationhalf-life,steadystateconditionsshouldbeachievedafter4weeks,asconfirmedbythe

meanpeakplasmalevelsofeflavexobtainedafterasingledose(37±8pg/ml)andaftera4weekmultiple-regimen

(101±43pg/ml)for0.5eflavexdose.

Tendaysafteradministrationabout18%and72%ofthedoseisrecoveredinurineandfaeces,respectively.Unchanged

eflavexinurineaccountsfor2-3%ofthedose.

Linearity/Non-linearity

Thepharmacokineticprofileislinearupto7mgperday.

5.3Preclinicalsafetydata

Almostallthefindingsnotedthroughouttheseriesofpreclinicalsafetystudiesareaconsequenceofthecentral

dopaminergiceffectsorthelong-lastinginhibitionofPRLinspecies(rodents)withaspecifichormonalphysiology

differenttoman.Preclinicalsafetystudiesofeflavexindicatealargesafetymarginforthiscompoundinrodentsand

inmonkeys,aswellasalackofteratogenic,mutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Anhydrouslactose

L-Leucin

Magnesiumstearate(E572)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfrommoisture.

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6.5Natureandcontentsofcontainer

Brownglassbottles(typeIII)thatcontainadesiccationcapsulewithsilicagel.Thebrownglassbottlehasan

induction-sealedchildproofaluminiummembraneandachildproofHDPEtop.Externalbox.

Packagingsizes:2,8,14,15,16,20,28,30,32,40,48,50,60,90,96,100.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NortonWaterford tradingasIVAXPharmaceuticalsIreland

Unit301

IDAIndustrialPark

CorkRoad

Waterford

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA436/44/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thFebruary2008

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