EFLAVEX

Main information

  • Trade name:
  • EFLAVEX Tablets 1 Milligram
  • Dosage:
  • 1 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EFLAVEX Tablets 1 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0436/044/001
  • 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)

PA0436/044/001

CaseNo:2080172

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NortonWaterford

T/AIVAXPharmaceuticalsIreland,Unit301,IDAIndustrialPark,CorkRoad,Waterford,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Eflavex1mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom29/03/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Eflavex1mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains1mgcabergoline.

Excipient:lactose75.3mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Thetabletcanbedividedintoequalhalves.

White,oval-shaped,biconvextabletscontaining1mgcabergoline.Eachtabletisscoredonbothsidesandhas‘CBG’

and‘1’ontheothersideofthebreakline.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofParkinson’sdisease:

Iftreatmentwithadopamineagonistisbeingconsidered,cabergolineisindicatedassecondlinetherapyinpatients

whoareintolerantorfailtreatmentwithanon-ergotcompound,asmonotherapy,orasadjunctivetreatmenttolevodopa

plusdopa-decarboxylaseinhibitor,inthemanagementofthesignsandsymptomsofParkinson'sdisease.

Treatmentshouldbeinitiatedunderspecialistsupervision.Thebenefitofcontinuedtreatmentshouldberegularly

reassessed,takingintoaccounttheriskoffibroticreactionsandvalvulopathy(seesections4.3,4.4and4.8).

4.2Posologyandmethodofadministration

Cabergolineistobeadministeredbytheoralroute.Inordertoreducetheriskofgastrointestinalundesirableeffectsit

isrecommendedthatcabergolineistakenwithmealsforalltherapeuticindications.

Adultsandelderlypatients

Asexpectedfordopamineagonists,doseresponseforbothefficacyandundesirableeffectsappearstobelinkedto

individualsensitivity.Optimizationofdoseshouldbeobtainedthroughslowinitialdosetitration,fromstartingdoses

of0.5mgcabergoline(denovopatients)and1mgcabergoline(patientsonLdopa)daily.Thedosageofconcurrent

levodopamaybegraduallydecreased,whilethedosageofcabergolineisincreased,untiltheoptimumbalanceis

determined.Inviewofthelonghalf-lifeofthecompound,incrementsofthedailydoseof0.5-1mgcabergolineshould

bedoneatweekly(initialweeks)orbi-weeklyintervals,uptooptimaldoses.

Therecommendedtherapeuticdosageis2to3mgcabergoline/dayasadjuvanttherapytolevodopa/carbidopa.The

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Useinchildrenandadolescents

ThesafetyandefficacyofcabergolinehasnotbeeninvestigatedinchildrenoradolescentsasParkinson’sdiseasedoes

notaffectthispopulation.

Useinpatientswithhepaticorrenaldysfunction

Forpatientswithseverehepaticdysfunctionorendstagerenalfailureseesection4.3and4.4.

4.3Contraindications

Pre-eclampsia,eclampsia

Post-partumhypertensionoruncontrolledhypertension.

Hypersensitivitytocabergoline,otherergotalkaloidsortoanyoftheexcipients.

Severeimpairmentofliverfunction

Historyofadversepulmonaryreactions,suchaspleuritisandfibrosis,associatedwithuseofdopamineagonist.

Historyofpericardialandretroperitonealfibroticdisorders.

Historyofpsychosisorriskofpost-partumpsychosis.

Forlongtermtreatment,evidenceofcardiacvalvulopathyofanyvalveasdeterminedbypre-treatment

echocardiography

4.4Specialwarningsandprecautionsforuse

General

Theassessmentofsafetyandefficacyofcabergolineislimitedinpatientswithrenalandhepaticdisease.Aswithother

ergotalkaloids,cabergolineshouldbegivenwithcautiontosubjectswithcardiovasculardisease,hypotension,

Raynaud'ssyndrome,pepticulcerorgastrointestinalbleeding.Theeffectsofalcoholonoveralltolerabilityof

cabergolinearecurrentlyunknown.

Cabergolineshouldbegivenwithcautiontopatientswithahistoryofpsychoticdisorders,ahistoryofseriousor

psychoticmentaldiseaseorwherethereisariskofpost-partumpsychosis.

FibrosisandCardiacValvulopathyandpossiblyrelatedclinicalphenomena:

Fibroticandserosalinflammatorydisorderssuchaspleuritis,pleuraleffusion,pleuralfibrosis,pulmonaryfibrosis,

pericarditis,pericardialeffusion,cardiacvalvulopathyinvolvingoneormorevalves(aortic,mitralandtricuspid)or

retroperitonealfibrosishaveoccurredafterprolongedusageofergotderivativeswithagonistactivityattheserotonin

receptor,suchascabergoline.Insomecases,symptomsormanifestationsofcardiacvalvulopathyimproved

afterdiscontinuationofcabergoline.Erythrocytesedimentationrate(ESR)hasbeenfoundtobeabnormallyincreased

inassociationwithpleuraleffusion/fibrosis.Chestx-rayexaminationisrecommendedincasesofunexplainedESR

increasestoabnormalvalues.

Serumcreatinemeasurementscanalsobeusedtohelpinthediagnosisoffibroticdisorder.

Valvulopathyhasbeenassociatedwithcumulativedoses,therefore,patientsshouldbetreatedwiththelowesteffective

dose.Ateachvisit,theriskbenefitprofileofcabergolinetreatmentforthepatientshouldbereassessedtodeterminethe

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Beforeinitiatinglongtermtreatment:

Allpatientsshouldundergoacardiovascularevaluation,includingechocardiogram,toassessthepotentialpresenceof

asymptomaticvalvulardisease.Itisalsoappropriatetoperformbaselineinvestigationsoferythrocytesedimentation

rateorotherinflammatorymarkers,lungfunction/chestx-rayandrenalfunctionpriortoinitiationoftherapy.In

patientswithvalvularregurgitation,itisnotknownwhethercabergolinetreatmentmightworsentheunderlying

disease.Iffibroticvalvulardiseaseisdetected,thepatientshouldnotbetreatedwithcabergoline.(SeeSection4.3).

Duringlongtermtreatment:

Fibroticdisorderscanhaveaninsidiousonsetandpatientsshouldberegularlymonitoredforpossiblemanifestationsof

progressivefibrosis.Thereforeduringtreatment,attentionshouldbepaidtothesignsandsymptomsof:

Pleuropulmonarydisease,suchasdyspnoea,shortnessofbreath,persistentcough,orchestpain.

Renalinsufficiencyorureteral/abdominalvascularobstructionthatmayoccurwithpainintheloin/flank,andlower

limboedema,aswellasanypossibleabdominalmassesortendernessthatmayindicateretroperitonealfibrosis.

Cardiacfailurecasesofvalvularandpericardialfibrosishaveoftenmanifestedascardiacfailure.Therefore,valvular

fibrosis(andconstrictivepericarditis)shouldbeexcludedifsuchsymptomsoccur.

Clinicaldiagnosticmonitoringfordevelopmentoffibroticdisease,asappropriate,isessential.Followingtreatment

initiation,thefirstechocardiogrammustoccurwithin3-6months,thereafter,thefrequencyofechocardiographic

monitoringshouldbedeterminedbyappropriateindividualclinicalassessmentwithparticularemphasisontheabove-

mentionedsignsandsymptoms,butmustoccurataleastevery6to12months.

Cabergolineshouldbediscontinuedifanechocardiogramrevealsneworworsenedvalvularregurgitation,valvular

restrictionorvalveleafletthickening.(SeeSection4.3)

Theneedforotherclinicalmonitoring(e.g.,physicalexaminationincludingcardiacauscultation,X-ray,CTscan)

shouldbedeterminedonanindividualbasis.

Additionalappropriateinvestigationssuchaserythrocytesedimentationrate,andserumcreatininemeasurements

shouldbeperformedifnecessarytosupportadiagnosisoffibroticdisorder.

Hypotension:

Symptomatichypotensioncanoccurwithin6hoursfollowingadministrationofcabergoline:particularattentionshould

bepaidwhenadministeringcabergolineconcomitantlywithothermedicinalproductknowntolowerbloodpressure.

Becauseofitseliminationhalf-lifehypotensiveeffectsmaypersistforafewdaysaftercessationoftherapy.

Monitoringoftreatmentwithregularchecksofbloodpressureisrecommendedinthefirst3-4daysafterinitiationof

treatment.

CNS:Cabergolinehasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,particularlyinpatients

withParkinson'sdisease.Suddenonsetofsleepduringactivities,insomecaseswithoutawarenessorwarningsigns,

hasbeenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhiledrivingor

operatingmachinesduringtreatmentwithcabergoline.Patientswhohaveexperiencedsomnolenceand/oranepisodeof

suddensleeponsetmustrefrainfromdrivingoroperatingmachines.Furthermoreareductionofdosageortermination

oftherapymaybeconsidered.

RenalInsufficiency:Nooveralldifferencesinthepharmacokineticsofcabergolinewereobservedinmoderatetosevere

renaldisease.Thepharmacokineticsofcabergolinehasnotbeenstudiedinpatientshavingend-stagerenalfailure,orin

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HepaticInsufficiency:Cabergolinepharmacokineticsinpatientswithmildtomoderatedysfunction(Child-Pugh

score<10)weresimilartothosedeterminedinpreviousstudiesinsubjectswithnormalhepaticfunction.However,

patientswiththemostseveredysfunction(Child-Pughscore>10)showedincreasedAUCvalues(>200%).These

patientsshouldbedosedwithcaution,anditisrecommendedthatdailydoseshouldbelimitedtonomorethan1mg.

Other

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson’sdisease,includingcabergoline.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusenotrecommended

Elevatedplasmalevelsofbromocriptinehavebeenobservedincombinationwithmacrolideantibiotics(suchas

erythromycin).Effectsofmacrolideantibioticsoncabergoline’splasmalevelswhenadministeredsimultaneouslyhave

notbeenstudied.Thecombinationshouldbeavoided,asitmayresultinelevatedcabergolineplasmalevels.

Cabergolineactsthroughdirectstimulationofdopaminereceptors.Consequently,itshouldnotbecombinedwith

medicinalproductswithadopamineantagonisticeffect(suchasphenothiazines,butyrophenones,thioxanthenes,

metoclopramide).

Noinformationisavailableaboutpossibleinteractionsbetweencabergolineandotherergotalkaloids.Therefore,long-

termtreatmentwithcabergolineisnotadvisedincombinationwiththesemedicinalproducts.

Precautions

Interactionswithothermedicinalproductsthatreducebloodpressureshouldbetakenintoconsideration.

NopharmacokineticinteractionswithL-dopaorselegilinehavebeenobservedinstudiesofpatientswithParkinson’s

disease.Pharmacokineticinteractionswithothermedicinalproductscannotbepredictedbasedonavailableinformation

aboutthemetabolismofcabergoline.

4.6Pregnancyandlactation

Pregnancy

Beforecabergolineadministration,pregnancyshouldbeexcludedandaftertreatmentshouldbepreventedforatleast

onemonth.

Cabergolinehasbeenshowntocrosstheplacentainrats.Itisnotknownwhetherthisoccursinhumans.Dataona

limitednumberofpregnancies(n=100),generallytakenduringthefirst8weeksafterconception,donotindicate

cabergolinetobeassociatedwithanincreasedriskofabortion,prematuredelivery,multiplepregnancyorcongenital

abnormalities.Todate,nootherrelevantepidemiologicaldataisavailable.Animalstudiesindicatenodirectorindirect

harmfuleffectswithrespecttopregnancy,embryonal/foetaldevelopment,parturitionorpost-nataldevelopment.

Becauseofthelimitedexperienceoftheuseofcabergolineinpregnancy,cabergolineshouldbewithdrawnbeforea

plannedpregnancy.Ifthepatientbecomespregnantduringtreatment,cabergolineshallbeimmediatelywithdrawn.

Duringpregnancy,thesepatientsmustbecarefullymonitoredforanypregnancy-inducedpituitaryenlargement.

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Cabergolinerestoresovulationandfertilityinwomenwithhyperprolactinaemichypogonadism:sincepregnancymight

occurpriortoreinitiationofmenses,pregnancytestingisrecommendedasappropriateduringtheamenorrhoeicperiod

and,oncemensesarereinitiated,everytimeamenstrualperiodisdelayedbymorethanthreedays.Womennotseeking

pregnancyshouldbeadvisedtouseeffectivenon-hormonalcontraceptionduringtreatmentandaftercabergoline

withdrawal.Becauseoflimitedexperienceonthesafetyoffoetalexposuretocabergoline,itisadvisablethatwomen

seekingpregnancyconceiveatleastonemonthaftercabergolinediscontinuationgiventhatovulatorycyclespersistin

somepatientsfor6monthsafterwithdrawal.Shouldpregnancyoccurduringtreatment,cabergolineistobe

discontinued.Asaprecautionarymeasure,womenwhobecomepregnantshouldbemonitoredtodetectsignsof

pituitaryenlargementsinceexpansionofpre-existingpituitarytumoursmayoccurduringgestation.

Contraceptionshouldbecontinuedforatleast4weeksafterstoppingcabergoline.

Lactation

Cabergolineshouldnotbeadministeredtomotherswhoelecttobreastfeedtheirinfantssinceitpreventslactation.No

informationisavailableontheexcretionofactivesubstanceinmaternalmilkbutinratscabergolineand/orits

metabolitesareexcretedinthemilk.

Lactationshouldbeavoidedwhentakingcabergoline.

4.7Effectsonabilitytodriveandusemachines

Cabergolinereducesbloodpressure,whichmayimpairthereactionsofcertainpatients.Thisshouldbetakeninto

accountinsituationsrequiringintenseawareness,suchaswhendrivingacaroroperatingmachinery.

Patientstreatedwithcabergolineandpresentingwithsomnolenceand/orsuddensleepepisodesmustbeinformedto

refrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersatriskofserious

injuryordeath,untilsuchrecurrentepisodesandsomnolencehaveresolved(seesection4.4).

4.8Undesirableeffects

About1070parkinsonianpatientshavereceivedcabergolineasadjuvanttherapytoL-dopainclinicalstudies;ofthese

74%hadatleastoneadverseevent,mainlyofmildtomoderateseverityandtransientinnature,andrequiring

discontinuationinasmallproportionofcases.

Nervoussystemdisorders:

Inthemajorityofcases(51%),eventswererelatedtothenervoussystem:mostfrequentlyreportedeventswere

dyskinesia,dizziness,hyperkinesia,hallucinationsorconfusion.

Gastrointestinaldisorders:

Thegastrointestinalsystemwasinvolvedin33%ofcases:eventsmostfrequentlyreportedwerenausea,vomiting,

dyspepsiaandgastritis.

Cardiacdisorders:

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Respiratory,thoracicandmediastinaldisorders:

Therespiratorysystemwasinvolvedin13%ofcases,symptomaticpleuraleffusion/fibrosisbeingreportedwitha

frequency<2%.

Therehavebeenreportsoffibroticandserosalinflammatoryconditions,suchaspleuritis,pleuraleffusion,pleural

fibrosis,pulmonaryfibrosis,pericarditis,pericardialeffusion,cardiacvalvulopathyandretroperitonealfibrosis,in

patientstakingcabergoline(see‘Specialwarningsandspecialprecautionsforuse’).Theincidenceofvalvulopathy

withcabergolineisnotknown,howeverbasedonrecentstudiesoftheprevalenceofvalvularregurgitation(themost

sensitiveechocardiographicmarkerforrestrictivevalvulopathy),theprevalenceofregurgitation(virtuallyallcases

asymptomatic)potentiallyattributabletocabergolinemaybeintherangeof20%orgreater.

Thereislimitedinformationavailableonthereversibilityofthesereactions.

Otheradverseeventsexpectedforthepharmacologicalclass,inviewofthevasoconstrictiveproperties,includeangina

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

expectedforthepharmacologicalclass,peripheraloedemaoccurredin6%ofpatients.

Gastricupsetwasmorefrequentinfemalethaninmalepatients,whileCNSeventsweremorefrequentintheelderly.

Abloodpressuredecreaseofclinicalrelevancewasobservedmainlyonstandinginaminorityofpatients.Theeffect

wasmainlyevidentinthefirstweeksoftherapy.NeithermodificationofheartratenorconsistentchangesofECG

tracingwereobservedduringcabergolinetreatment.

Alterationsinstandardlaboratorytestsareuncommonduringlongtermtherapywithcabergoline.Inclinicalstudies,

increasesoftriglyceridesgreaterthan30%abovetheupperlimitofthelaboratoryreferencerangewereobservedin

6.8%ofthecabergoline-treatedpatientswhohadvalueswithinthenormalrangeatbaseline.Inmostcasesthe

increasesweretransient.Noclearindicationsofincreasesovertimeorsignificantshiftsfromnormaltoabnormal

valueswereobservedintheoverallgroupofpatientstreatedwithcabergoline.Aclinicallyrelevantdecreasein

haemoglobin,haematocritand/orredbloodcellcount>15%Vsbaseline)wasobservedatleastoncein6.8%ofclinical

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Post-marketingSurveillance:

Cabergolineisassociatedwithsomnolenceandhasbeenassociateduncommonlywithexcessivedaytimesomnolence

andsuddensleeponsetepisodes.

PatientstreatedwithdopamineagonistsfortreatmentofParkinson’sdisease,includingcabergoline,especiallyathigh

doses,havebeenreportedasshowingpathologicalgambling,increasedlibidoandhypersexuality,generallyreversible

uponreductionofthedoseortreatmentdiscontinuation.

Thefollowingeventshavebeenreportedinassociationwithcabergoline:

Cardiacdisorders

Verycommon(1/10)

Common(1/100to<1/10)

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

Cardiacvalvulopathy(includingregurgitation)andrelated

disorders(pericarditisandpericardialeffusion)

Angina

Erythromelalgia

Bloodandlymphaticsystem

disorders

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

erythrocytecount

Nervoussystemdisorders

Verycommon(1/10)

Common(1/100to<1/10)

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

Drowsiness,Sleepdisorders,hallucinations,confusion

Episodeswherethepatientsuddenlyfallsasleep

Respiratory,thoracicand

mediastinaldisorders

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

Gastrointestinaldisorders

Verycommon(1/10)

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

Vomiting,dyspepsia,gastritis,constipation.

Generaldisordersand

administrationsiteconditions

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Other:

Adverseeventshavebeenreportedwithlowerdosesofcabergoline(0.25–2mgperweek)thatarenotlistedabove

including:

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

Cabergolineisasyntheticergotalkaloidandanergolinederivatewithlong-actingdopamineagonistandprolactin-

inhibitingproperties.AcentraldopaminergiceffectviaD2-receptorstimulationisachievedthroughhigherdosesthan

Cardiacdisorders

Common(1/100to<1/10) Palpitations

Nervoussystemdisorders

Common(1/100to<1/10) Depression,headache,fatigue,paresthesia,somnolence.

Eyedisorders

Uncommon(1/1000to<1/100) Hemianopsia

Gastrointestinaldisorders

Common(1/100to<1/10) Constipation

Skinandsubcutaneoustissue

disorders

Common(1/100to<1/10) Facialredness

Musculoskeletalandconnective

tissuedisorders

Rare(1/10000to<1/1000) Crampinfingersandcalves

Vasculardisorders

Uncommon(1/1000to<1/100)

Rare(1/10000to<1/1000) Nosebleeding

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Controlledclinicalstudieshavedemonstratedthatcabergolineiseffectiveatanaveragedoseof4mg/dayfollowing

titration(upto5-6mgcabergoline/dayinthedifferentstudies).Cabergolinereducesdailyfluctuationsinthemotor

functioninpatientswithParkinson’sdiseasethatarebeingtreatedwithlevodopa/carbidopa.Innewlydiagnosed

patients,cabergolineadministeredasmonotherapyhasbeenshowntoproducesomewhatlessfrequentclinical

improvementcomparedwithlevodopa/carbidopa.

Withregardtotheendocrineeffectsofcabergolinenotrelatedtotheantiprolactinaemiceffect,availabledatafrom

humansconfirmtheexperimentalfindingsinanimalsindicatingthatthetestcompoundisendowedwithavery

selectiveactionwithnoeffectonbasalsecretionofotherpituitaryhormonesorcortisol.

Thepharmacodynamicactionsofcabergolinenotcorrelatedwiththetherapeuticeffectonlyrelatetobloodpressure

decrease.Themaximalhypotensiveeffectofcabergolineassingledoseusuallyoccursduringthefirst6hoursafter

activesubstanceintakeandisdose-dependentbothintermsofmaximaldecreaseandfrequency.

5.2Pharmacokineticproperties

Absorption

Afteroraladministrationcabergolineisrapidlyabsorbedfromthegastrointestinaltractasthepeakplasma

concentrationisreceivedwithin0.5to4hours.

Fooddoesnotappeartoaffectabsorptionanddispositionofcabergoline.

Distribution

“In-vitro”experimentsshowedthatcabergolineatconcentrationsof0.1–10ng/mlis41-42%boundtoplasma

proteins.

Biotransformation

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

additionalmetabolitesareidentifiedinurine,whichaccountoverallforlessthan3%ofthedose.Themetaboliteshave

beenfoundtobemuchlesspotentthancabergolineininhibitingprolactinsecretion“in-vitro”.

Elimination

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

hyperprolactinaemicpatients.

Onthebasisoftheeliminationhalf-life,steadystateconditionsshouldbeachievedafter4weeks,asconfirmedbythe

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

(101±43pg/ml)for0.5cabergolinedose.

Tendaysafteradministrationabout18%and72%ofthedoseisrecoveredinurineandfaeces,respectively.Unchanged

cabergolineinurineaccountsfor2-3%ofthedose.

Linearity/Non-linearity

Thepharmacokineticprofileislinearupto7mgperday.

5.3Preclinicalsafetydata

Almostallthefindingsnotedthroughouttheseriesofpreclinicalsafetystudiesareaconsequenceofthecentral

dopaminergiceffectsorthelong-lastinginhibitionofPRLinspecies(rodents)withaspecifichormonalphysiology

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Preclinicalsafetystudiesofcabergolineindicatealargesafetymarginforthiscompoundinrodentsandinmonkeys,as

wellasalackofteratogenic,mutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Anhydrouslactose

L-Leucine

Magnesiumstearate(E572)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfrommoisture.

Thedryingcapsuleorbagwithsilicagelmustnotberemovedfromthebottle.

6.5Natureandcontentsofcontainer

Brownglassbottles(typeIII)thatcontainadesiccationcapsuleorbagwithsilicagel.Thebrownglassbottlehasan

induction-sealedchildproofaluminiummembraneandachildproofHDPEorPolypropylenetop.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

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29February2008

Dateoflastrenewal:7May2009

10DATEOFREVISIONOFTHETEXT

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