CABERGOLINE 0.5 MILLIGRAM TABLETS

Main information

  • Trade name:
  • CABERGOLINE 0.5 MILLIGRAM TABLETS
  • Dosage:
  • 0.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CABERGOLINE 0.5 MILLIGRAM TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1130/014/001
  • Authorization date:
  • 08-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1130/014/001

CaseNo:2062932

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ArrowGenericsLimited

Unit2,EastmanWay,Stevenage,Hertfordshire,SG14SZ,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cabergoline0.5mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom16/03/2010until07/02/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cabergoline0.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains0.5mgcabergoline.

Excipient:lactosemonohydrate75mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Awhitetooff-white,capsule-shapedtablet,embossedwith‘C|5’ononesideand‘partialscore>’ontheotherside.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inhibitionoflactationformedicalreasons.

Hyperprolactimaemicdisorders.

Prolactinsecretingpituitaryadenomas.

Idiopathichyperprolactinaemia.

Itisrecommendedthatthemedicinalproductisinitiallyprescribedbyanappropriatespecialistorafterconsultinga

specialist.

4.2Posologyandmethodofadministration

Cabergolineistobeadministeredbytheoralroute.

Inordertoreducetheriskofgastrointestinalundesirableeffectsitisrecommendedthatcabergolinebepreferably

takenwithmealsforallthetherapeuticindications.

Treatmentofhyperprolactinaemicdisorders

Therecommendedinitialdosageofcabergolineis0.5mgperweekgiveninone(single0.5mg)ortwo(separate0.25

mg)doses(e.g.onMondayandThursday)perweek.

Theweeklydoseshouldbeincreasedgradually,preferablybyadding0.5mgperweekatmonthlyintervalsuntilan

optimaltherapeuticresponseisachieved.

Thetherapeuticdosageisusually1mgperweekandrangesfrom0.25mgto2mgcabergolineperweek.

Dosesofcabergolineupto4.5mgperweekhavebeenusedinhyperprolactinaemicpatients.Themaximumdailydose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 2

Theweeklydosemaybegivenasasingleadministrationordividedintotwoormoredosesperweekaccordingto

patienttolerability.Divisionoftheweeklydoseintomultipleadministrationsisadvisedwhendoseshigherthan1mg

perweekaretobegivensincethetolerabilityofdosesgreaterthan1mgtakenasasingleweeklydosehasbeen

evaluatedonlyinafewpatients.

Patientsshouldbeevaluatedduringdoseescalationtodeterminethelowestdosagethatproducesthetherapeutic

response.

Forinhibitionoflactation

Cabergolineshouldbeadministeredwithinthefirst24hourspost-partum.Therecommendedtherapeuticdosageis

1mgcabergolinegivenasadingledose.

Useinchildrenandadolescents

Thesafetyandefficacyofcabergolinehasnotbeenestablishedinsubjectslessthan16yearsofage.

Elderly

Asaconsequenceoftheindicationsforwhichthisstrengthofcabergolineispresentlyproposed,experienceinthe

elderlyisverylimited.Availabledatadonotindicateaspecialrisk.

RenalInsufficiency

Theassessmentofsafetyandefficacyofcabergolineislimitedinpatientswithrenaldisease.Nooveralldifferencesin

thepharmacokineticsofcabergolinewereobservedinmoderatetosevererenaldisease.Thepharmacokineticsof

cabergolinehasnotbeenstudiedinpatientshavingend-stagerenalfailure,orinpatientsonhaemodialysis;these

patientsshouldbetreatedwithcaution.

HepaticInsufficiency

Theassessmentofsafetyandefficacyofcabergolineislimitedinpatientswithhepaticdisease.Cabergoline

pharmacokineticsinpatientswithmildtomoderatedysfunction(Child-Pughscore<10)weresimilartothose

determinedinpreviousstudiesinsubjectswithnormalhepaticfunction.However,patientswiththemostsevere

dysfunction(Child-Pughscore>10)showedincreasedAUCvalues(>200%).Thesepatientsshouldbedosedwith

caution,anditisrecommendedthatthedoseshouldbelimitedtonomorethan1mg/day.

4.3Contraindications

Hypersensitivitytocabergoline,anyergotalkaloidortoanyoftheexcipients

Pre-eclampsia,eclampsia

Uncontrolledhypertension,post-partumhypertension

Historyofpulmonary,pleural,,pericardialandretroperitonealfibroticdisordersespeciallyifassociatedwith

theuseofdopamineagonists.

Evidenceofcardiacvalvulopathyasdeterminedbypretreatmentechocardiography.

Historyofpsychosisorriskofpostpartumpsychosis

4.4Specialwarningsandprecautionsforuse

General

Aswithotherergotalkaloids,cabergolineshouldbegivenwithcautiontosubjectswithcardiovasculardisease,

hypotension,Raynaud'ssyndrome,pepticulcerorgastrointestinalbleeding.

Theeffectsofalcoholontheoveralltolerabilityofcabergolinearecurrentlyunknown.

Hypotension

Symptomatichypotensioncanoccurwithcabergoline,particularlywhentakenconcomitantlywithothermedicinal

productsknowntolowerbloodpressure.

Monitoringoftreatmentwithregularchecksofbloodpressureisrecommendedinthefirst3-4daysafterinitiationof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 3

CNS

Somnolence:cabergolinehasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,particularlyin

patientswithParkinson’sdisease.Suddenonsetofsleepduringdailyactivities,insomecaseswithoutawarenessor

warningsigns,hasbeenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhile

drivingoroperatingmachinesduringtreatmentwithcabergoline.Patientswhohaveexperiencedsomnolenceand/oran

episodeofsuddensleeponsetmustrefrainfromdrivingoroperatingmachinesduringtreatmentwithcabergoline(see

section4.7).Further,areductionofdosageorterminationoftreatmentmaybeconsidered.

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson’sdisease,includingcabergoline.

Treatmentofhyperprolactinaemicdisorders

Sincehyperprolactinaemiawithamenorrhoeaandinfertilitymaybeassociatedwithpituitarytumours,theunderlying

causeofthehyperprolactinaemiashouldbeinvestigatedbeforetreatmentwithcabergolineiscommenced.

Monitoringofserumprolactinlevelsatmonthlyintervalsisadvisedsince,oncetheeffectivetherapeuticdosage

regimenhasbeenreached,serumprolactinnormalisationisusuallyobservedwithintwotofourweeks.

Aftercabergolinewithdrawal,recurrenceofhyperprolactinaemiaisusuallyobserved.However,persistentsuppression

ofprolactinlevelshasbeenobservedforseveralmonthsinsomepatients.

Fibrosisandcardiacvalvulopathyandpossiblyrelatedclinicalphenomena:

Fibroticandserosalinflammatorydisorderssuchaspleuritis,pleuraleffusion,pleuralfibrosis,pulmonaryfibrosis,

pericarditis,pericardialeffusion,cardiacvalvulopathyinvolvingoneormorevalves(aortic,mitralandtricuspid)or

retroperitonealfibrosishaveoccurredafterprolongedusageofergotderivativeswithagonistactivityattheserotonin

receptor,suchascabergoline.Insomecases,symptomsormanifestationsofcardiacvalvulopathyimproved

afterdiscontinuationofcabergoline.

Erythrocytesedimentationrate(ESR)hasbeenfoundtobeabnormallyincreasedinassociationwithpleural

effusion/fibrosis.Chestx-rayexaminationisrecommendedincasesofunexplainedESRincreasestoabnormalvalues.

Valvulopathyhasbeenassociatedwithcumulativedoses,therefore,patientsshouldbetreatedwiththelowesteffective

dose.Ateachvisit,theriskbenefitprofileofcabergolinetreatmentforthepatientshouldbereassessedtodeterminethe

suitabilityofcontinuedtreatmentwithcabergoline.

Beforeinitiatinglong-termtreatment:

Allpatientsmustundergoacardiovascularevaluation,includingechocardiogram,toassessthepotentialpresenceof

asymptomaticvalvulardisease.Itisalsoappropriatetoperformbaselineinvestigationsoferythrocytesedimentation

rateorotherinflammatorymarkers,lungfunction/chestX-rayandrenalfunctionpriortoinitiationoftherapy.

Inpatientswithvalvularregurgitation,itisnotknownwhethercabergolinetreatmentmightworsentheunderlying

disease.Iffibroticvalvulardiseaseisdetected,thepatientshouldnotbetreatedwithcabergoline(seesection4.3).

Duringlong-termtreatment:

Fibroticdisorderscanhaveaninsidiousonsetandpatientsshouldberegularlymonitoredforpossiblemanifestationsof

progressivefibrosis.

Therefore,duringtreatment,attentionshouldbepaidtothesignsandsymptomsof:

Pleuro-pulmonarydiseasesuchasdyspnoea,shortnessofbreath,persistentcoughorchestpain.

Renalinsufficiencyorureteral/abdominalvascularobstructionthatmayoccurwithpainintheloin/flankandlower

limboedemaaswellasanypossible abdominalmassesortendernessthatmayindicateretroperitonealfibrosis.

Cardiacfailure;casesofvalvularandpericardialfibrosishaveoftenmanifestedascardiacfailure.Therefore,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 4

Clinicaldiagnosticmonitoringfordevelopmentoffibroticdisorders,asappropriate,isessential.Followingtreatment

initiation,thefirstechocardiogrammustoccurwithin3-6months,thereafter,thefrequencyofechocardiographic

monitoringshouldbedeterminedbyappropriateindividualclinicalassessmentwithparticularemphasisontheabove-

mentionedsignsandsymptoms,butmustoccuratleastevery6to12months.

Cabergolineshouldbediscontinuedifanechocardiogramrevealsneworworsenedvalvularregurgitation,valvular

restrictionorvalveleafletthickening(seeSection4.3).

Theneedforotherclinicalmonitoring(e.g.physicalexaminationincluding,cardiacauscultation,Xray,CTscan)

shouldbedeterminedonanindividualbasis.

Additionalappropriateinvestigationssuchaserythrocytesedimentationrate,andserumcreatininemeasurements

shouldbeperformedifnecessarytosupportadiagnosisofafibroticdisorder.

Other

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Precautions

Pharmacokineticinteractionswithothermedicinalproductscannotbepredictedbasedonavailableinformationabout

themetabolismofcabergoline.

NopharmacokineticinteractionswithL-dopaorselegilinehavebeenobservedinstudiesofpatientswithParkinson’s

disease.

Concomitantusenotrecommended

Elevatedplasmalevelsofbromocriptinehavebeenobservedincombinationwithmacrolideantibiotics(suchas

erythromycin).Effectsofmacrolideantibioticsoncabergoline’splasmalevelswhenadministeredsimultaneouslyhave

notbeenstudied.Thecombinationshouldbeavoided,asitmayresultinelevatedcabergolineplasmalevels.

Cabergolineactsthroughdirectstimulationofdopaminereceptors.Consequently,itshouldnotbecombinedwith

medicinalproductswithadopamineantagonisticeffect(suchasphenothiazines,butyrophenones,thioxanthenes,

metoclopramide)

Noinformationisavailableaboutpossibleinteractionsbetweencabergolineandotherergotalkaloids.Therefore,long-

termtreatmentwithcabergolineisnotadvisedincombinationwiththesemedicinalproducts.

Interactionswithothermedicinalproductsthatreducebloodpressureshouldbetakenintoconsideration.

4.6Pregnancyandlactation

Pregnancy

Pregnancyshouldbeexcludedbeforecabergolineadministration,andshouldbepreventedforatleastonemonthafter

treatment.

Cabergolinehasbeenshowntocrosstheplacentainrats.Itisnotknownwhetherthisoccursinhumans.Dataona

limitednumberofpregnancies(n=100),generallytakenduringthefirst8weeksafterconception,donotindicate

cabergolinetobeassociatedwithanincreasedriskofabortion,prematuredelivery,multiplepregnancyorcongenital

abnormalities.Todate,nootherrelevantepidemiologicaldataareavailable.Animalstudiesindicatenodirector

indirectharmfuleffectswithrespecttopregnancy,embryonal/foetaldevelopment,parturitionorpost-natal

development.

Becauseofthelimitedexperienceoftheuseofcabergolineinpregnancy,cabergolineshouldbewithdrawnbeforea

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 5

Duringpregnancy,thesepatientsmustbecarefullymonitoredforanypregnancy-inducedpituitaryenlargement.

Cabergolinerestoresovulationandfertilityinwomenwithhyperprolactinaemichypogonadism:sincepregnancymight

occurpriortoreinitiationofmenses,pregnancytestingisrecommendedasappropriateduringtheamenorrhoeicperiod

and,oncemensesarereinitiated,everytimeamenstrualperiodisdelayedbymorethanthreedays.Whenstarting

dopaminergictreatment,womenmustbewarnedthatrestorationofovulationandfertilitymaybeimmediate(even

beforetheirfirstnormalmenstruation).Womennotseekingpregnancyshouldbeadvisedtouseeffectivenon-hormonal

contraceptionduringtreatmentandaftercabergolinewithdrawal.Becauseoflimitedexperienceonthesafetyoffoetal

exposuretocabergoline,itisadvisablethatwomenseekingpregnancyconceiveatleastonemonthaftercabergoline

discontinuationgiventhatovulatorycyclespersistinsomepatientsfor6monthsafterwithdrawal.Shouldpregnancy

occurduringtreatment,cabergolineistobediscontinued.Asaprecautionarymeasure,womenwhobecomepregnant

shouldbemonitoredtodetectsignsofpituitaryenlargementsinceexpansionofpre-existingpituitarytumoursmay

occurduringgestation.

Contraceptionshouldbecontinuedforatleast4weeksafterstoppingcabergoline.

Cabergolineshouldonlybeusedduringpregnancyifclearlyindicated.

Lactation

Cabergolineshouldnotbeadministeredtomotherswhoelecttobreast-feedtheirinfantssinceitpreventslactation.No

informationisavailableonexcretionoftheactivesubstanceinmaternalmilkbutinratscabergolineand/orits

metabolitesareexcretedinthemilk.

Breastfeedingshouldbeavoidedwhentakingcabergoline.

4.7Effectsonabilitytodriveandusemachines

Cabergolinereducesbloodpressure,whichmayimpairthereactionsofcertainpatients.Thisshouldbetakeninto

accountinsituationsrequiringintenseawareness,suchaswhendrivingacaroroperatingmachinery.

Patientsbeingtreatedwithcabergolineandpresentingwithsomnolenceand/orsuddensleepepisodesmustbe

informedtorefrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersat

riskofseriousinjuryordeath(e.g.operatingmachines)untilsuchrecurrentepisodesandsomnolencehaveresolved

(seealsosection4.4).

4.8Undesirableeffects

Theundesirableeffectsareusuallydose-dependent,andcanbereducedbydecreasingthedosegradually.

Inhibitionoflactation:

Approximately14%ofpatientsexperienceundesirableeffects.Themostcommonarelowbloodpressure(12%),

dizziness(6%)andheadaches(5%).Long-termtreatmentincreasesthefrequencyofundesirableeffectsto

approximately70%.

Post-marketingsurveillance(includingtreatmentwithdifferentstrengthsinParkinson’sDisease)

Fibroticreactions.Therehavebeenreportsoffibroticandserosalinflammatoryconditions,suchaspleuritis,pleural

effusion,pleuralfibrosis,pulmonaryfibrosis,pericarditis,pericardialeffusion,cardiacvalvulopathyandretroperitoneal

fibrosis,inpatientstakingcabergoline(see‘Specialwarningsandspecialprecautionsforuse’).

Theincidenceofcardiacvalvulopathywithcabergolineisnotknown.Howeverbasedonrecentstudiesofthe

prevalenceofvalvularregurgitation(themostsensitiveechocardiogaphicmarkerforrestrictivevalvulopathy),the

prevalenceofregurgitation(virtuallyallcasesasymptomatic)potentiallyattributabletocabergolinemaybeinthe

rangeof20%orgreater.Thereislimitedinformationavailableonthereversibilityofthesereactions.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 6

somnolenceandsuddensleeponsetepisodes.

Pathologicalgambling,increasedlibidoandhypersexuality.Patientstreatedwithdopamineagonistsfortreatment

ofParkinson’sdisease,includingcabergoline,especiallyathighdoses,havebeenreportedasshowingpathological

gambling,increasedlibidoandhypersexuality,generallyreversibleuponreductionofthedoseortreatment

discontinuation.

Thefollowingundesirableeffectshavebeenobservedduringtreatmentwithcabergolinewiththefollowing

frequencies:Verycommon( ≥1/10),Common(≥1/100to<1/10),uncommon(≥1/1,000to<1/100),rare(≥1/10,000to

<1/1,000),veryrare(<1/10,000)includingisolatedreports.

Investigations

Common Afallinhaemoglobinandhaematocrit

values,fallintheerythrocytecount,

increasesoftriglyceridesgreaterthan30%

abovetheupperlimitofthelaboratory

referencerange(mostlytransient)

Cardiacdisorders

Verycommon

Common

Orthostatichypotension(mainlyevidentin

thefirstweeksoftherapy).

Cardiacvalvulopathy(including

regurgitation)andrelateddisorders

(pericarditisandpericardialeffusion).

Angina,palpitations

Erythromelalgia

Nervoussystemdisorders

Verycommon

Common

Rare

Notknown(cannotbeestimatedfrom

Dyskinesia,dizziness,hyperkinesia.

Drowsiness,Sleepdisorders/somnolence,

hallucinations,confusion,depression,

headache,fatigue,paresthesia

Suddensleeponsetepisodes

Pathologicalgambling,increasedlibidoand

hypersexuality,generallyreversibleupon

reductionofthedoseortreatment

discontinuation.

Eyedisorders

Uncommon Hemianopia

Respiratory,thoracicand

mediastinaldisorders

Common Symptomaticpleuraleffusion/pulmonary

fibrosis/pleuritis

Gastrointestinaldisorders

Verycommon

Common Nausea

Vomiting,dyspepsia,gastritis,constipation.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 7

4.9Overdose

Thereisnoclinicalexperienceofoverdosing,butobservationsfromanimalexperimentssuggestthatsymptoms

resultingfromoverstimulationofdopaminereceptorscanbeexpected,suchasnausea,vomiting,reducedblood

pressure,confusion/psychosisorhallucinations.Whereindicated,measuresmustbetakentorestorebloodpressure.In

addition,withpronouncedsymptomsfromtheCNS(hallucinations),administrationofadopamineantagonistcanbe

necessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Prolactininhibitor

ATCcode:G02CB03

Cabergolineisasyntheticergotalkaloidandanergolinederivatewithlong-actingdopamineagonistandprolactin-

inhibitingproperties.AcentraldopaminergiceffectviaD2-receptorstimulationisachievedthroughhigherdosesthan

dosesthatreducethelevelsofserumprolactin.

Theprolactin-reducingeffectisdose-dependent,startingwithin3hoursandremainingfor2-3weeks.Thelong-acting

effectmeansthatasingledoseisgenerallysufficienttostoptheinitiationofmilksecretion.Intreatmentof

hyperprolactinaemia,theserumprolactinlevelsaregenerallynormalisedwithintwotofourweeksoftheoptimaldose

beingattained.Prolactincanstillbesignificantlyreducedseveralmonthsafterwithdrawalofthetreatment.

Withregardtotheendocrineeffectsofcabergolinenotrelatedtotheantiprolactinaemiceffect,availabledatafrom

humansconfirmtheexperimentalfindingsinanimalsindicatingthatthetestcompoundisendowedwithavery

selectiveactionwithnoeffectonbasalsecretionofotherpituitaryhormonesorcortisol.

Thepharmacodynamicactionsofcabergolinenotcorrelatedwiththetherapeuticeffectonlyrelatetobloodpressure

decrease.Themaximalhypotensiveeffectofcabergolineassingledoseusuallyoccursduringthefirst6hoursafter

Notknown(cannotbeestimatedfrom

theavailabledata) femalethaninmalepatients.

Retroperitionealfibrosis

Skinandsubcutaneoustissue

disorders

Common Facialredness

Musculoskeletal,connectivetissue

andbonedisorders

Rare Crampinfingersandcalves

Vasculardisorders

Uncommon

Rare Nosebleeding

Fainting

Generaldisordersand

administrationsiteconditions

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 8

5.2Pharmacokineticproperties

Absorption

Afteroraladministrationcabergolineisrapidlyabsorbedfromthegastrointestinaltractasthepeakplasma

concentrationisreachedwithin0.5to4hours.

Fooddoesnotappeartoaffectabsorptionanddispositionofcabergoline.

Distribution

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

proteins.

Biotransformation

Inurine,themainmetaboliteidentifiedwas6-allyl-8-carboxy-ergoline,whichaccountedfor4-6%ofthedose.

Threeadditionalmetaboliteswereidentifiedinurine,whichaccountedoverallforlessthan3%ofthedose.The

metaboliteshavebeenfoundtobemuchlesspotentthancabergolineininhibitingprolactinsecretion“invitro”.

Elimination

Theeliminationhalf-lifeofcabergolineislong(63-68hoursinhealthyvolunteersand79-115hoursin

hyperprolactinaemicpatients.

Onthebasisoftheeliminationhalf-life,steadystateconditionsshouldbeachievedafter4weeks,asconfirmedbythe

meanpeakplasmalevelsofcabergolineobtainedafterasingledose(378pg/ml)andaftera4weekmultipleregimen

(10143pg/ml)for0.5mgcaberglinedose.

Tendaysafteradministrationabout18%and72%ofthedoseisrecoveredinurineandfaeces,respectively.

Unchangedcabergolineinurineaccountsfor2-3%ofthedose.

Linearity/Non-linearity

Thepharmacokineticprofileislinearupto7mgperday.

5.3Preclinicalsafetydata

Almostallthefindingsnotedthroughouttheseriesofpreclinicalsafetystudiesareaconsequenceofthecentral

dopaminergiceffectsorthelong-lastinginhibitionofPRLinspecies(rodents)withaspecifichormonalphysiology

differenttoman.Preclinicalsafetystudiesofcabergolineindicatealargesafetymarginforthiscompoundinrodents

andinmonkeys,aswellasalackofteratogenic,mutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Leucine

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 9

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackagetoprotectfrommoisture.

6.5Natureandcontentsofcontainer

TypeIIIamberglassbottleswithapolypropylenescrewcap.

Acylindricaltubeorsachetcontainingdesiccant(silicagel)isprovidedineachbottle.

Eachbottlecontains2,4,8,20,28,30,40&80tabletsandisenclosedinanoutercardboardcarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

ArrowGenericsLimited,

Unit2,EastmanWay,

Stevenage,

HertsSG14SZ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1130/014/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

February2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2062932 page number: 10