CABEREX 2 MILLIGRAM TABLETS

Main information

  • Trade name:
  • CABEREX 2 MILLIGRAM TABLETS
  • Dosage:
  • 2 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CABEREX 2 MILLIGRAM TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1130/010/002
  • 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)

PA1130/010/002

CaseNo:2062932

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ArrowGenericsLimited

Unit2,EastmanWay,Stevenage,Hertfordshire,SG14SZ,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Caberex2mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

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

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Caberex2mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains2mgcabergoline.

Excipient:lactosemonohydrate149mg.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Awhitetooff-white,capsule-shapedtablet,embossedwith‘CE|2’ononesideand‘partialscore>’ontheotherside.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofParkinson’sdisease

Iftreatmentwithadopamineagonistisbeingconsidered,cabergolineisindicatedassecondlinetherapyinpatients

whoareintolerantorfailtreatmentwithanon-ergotcompound,asmonotherapy,orasadjunctivetreatmenttolevodopa

plusdopa-decarboxylaseinhibitor,inthemanagementofthesignsandsymptomsofParkinson’sdisease.

Treatmentshouldbeinitiatedunderspecialistsupervision.Thebenefitofcontinuedtreatmentshouldberegularly

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

4.2Posologyandmethodofadministration

Cabergolineistobeadministeredbytheoralroute.

Inordertoreducetheriskofgastrointestinalundesirableeffectsitisrecommendedthatcabergolineistakenwithmeals

foralltherapeuticindications.

Adultsandelderlypatients

Asexpectedfordopamineagonists,doseresponseforbothefficacyandsideeffectsappearstobelinkedtoindividual

sensitivity.

Optimizationofdoseshouldbeobtainedthroughslowinitialdosetitration,fromstartingdosesof0.5mgcabergoline

(denovopatients)and1mgcabergoline(patientsonLdopa)daily.Thedosageofconcurrentlevodopamaybe

graduallydecreased,whilethedosageofcabergolineisincreased,untiltheoptimumbalanceisdetermined.The

maximumdailydoseshouldnotexceed3mg/day . Inviewofthelonghalf-lifeofthecompound,incrementsofthe

dailydoseof0.5-1mgcabergolineshouldbemadeatweekly(initialweeks)orbi-weeklyintervals,uptooptimaldoses.

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Cabergolineshouldbegivenasasingledailydose.

Useinchildrenandadolescents

ThesafetyandefficacyofcabergolinehasnotbeeninvestigatedinchildrenoradolescentsasParkinson’sdiseasedoes

notaffectthispopulation.

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,toanyoftheexcipientsortoanyotherergotalkaloids.

Pre-eclampsia,eclampsia.

Uncontrolledhypertension,post-partumhypertension

Historyofpulmonary,pleural,,pericardialandretroperitonealfibroticdisordersespeciallyifassociatedwiththeuse

ofdopamineagonists.

Evidenceofcardiacvalvulopathyasdeterminedbypretreatmentechocardiography.

4.4Specialwarningsandprecautionsforuse

General

Aswithotherergotalkaloids,cabergolineshouldbegivenwithcautiontosubjectswithcardiovasculardisease,

hypotension,Raynaud’ssyndrome,pepticulcerorgastrointestinalbleeding.

Theeffectsofalcoholontheoveralltolerabilityofcabergolinearecurrentlyunknown.

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

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Beforeinitiatinglong-termtreatment:

Allpatientsmustundergoacardiovascularevaluation,includingechocardiogram,toassessthepotentialpresenceof

asymptomaticvalvulardisease.Itisalsoappropriatetoperformbaselineinvestigationsoferythrocytesedimentation

rateorotherinflammatorymarkers,lungfunction/chestX-rayandrenalfunctionpriortoinitiationoftherapy.

Inpatientswithvalvularregurgitation,itisnotknownwhethercabergolinetreatmentmightworsentheunderlying

disease.Iffibroticvalvulardiseaseisdetected,thepatientshouldnotbetreatedwith

Duringlong-termtreatment:

Fibroticdisorderscanhaveaninsidiousonsetandpatientsshouldberegularlymonitoredforpossiblemanifestationsof

progressivefibrosis.

Therefore,duringtreatment,attentionshouldbepaidtothesignsandsymptomsof:

Pleuro-pulmonarydiseasesuchasdyspnoea,shortnessofbreath,persistentcoughorchestpain.

Renalinsufficiencyorureteral/abdominalvascularobstructionthatmayoccurwithpainintheloin/flankandlower

limboedemaaswellasanypossible abdominalmassesortendernessthatmayindicateretroperitonealfibrosis.

Cardiacfailure;casesofvalvularandpericardialfibrosishaveoftenmanifestedascardiacfailure.Therefore,

valvularfibrosis(andconstrictivepericarditis)shouldbeexcludedifsuchsymptomsoccur.

Clinicaldiagnosticmonitoringfordevelopmentoffibroticdisorders,asappropriate,isessential.

Followingtreatmentinitiation,thefirstechocardiogrammustoccurwithin3-6months,thereafter,thefrequencyof

echocardiographicmonitoringshouldbedeterminedbyappropriateindividualclinicalassessmentwithparticular

emphasisontheabove-mentionedsignsandsymptoms,butmustoccuratleastevery6to12months.

Cabergolineshouldbediscontinuedifanechocardiogramrevealsneworworsenedvalvularregurgitation,valvular

restrictionorvalveleafletthickening(seeSection4.3).

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

shouldbedeterminedonanindividualbasis.

Additionalappropriateinvestigationssuchaserythrocytesedimentationrate,andserumcreatininemeasurements

shouldbeperformedifnecessarytosupportadiagnosisofafibroticdisorder.”

Hypotension

Symptomatichypotensioncanoccurwithin6hoursfollowingadministrationofcabergoline:particularattentionshould

bepaidwhenadministeringcabergolineconcomitantlywithothermedicalproductsknowntolowerbloodpressure.

Becauseofitseliminationhalf-lifehypotensiveeffectsmaypersistforafewdaysaftercessationoftherapy.

Monitoringoftreatmentwithregularchecksofbloodpressureisrecommendedinthefirst3-4daysafterinitiationof

treatment.

CNS

Cabergolineshouldbegivenwithcautiontopatientswithahistoryofpsychoticdisorders,ahistoryofseriousor

psychoticmentaldiseaseorwherethereisariskofpost-partumpsychosis.

Somnolence:cabergolinehasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,particularlyin

patientswithParkinson’sdisease.Suddenonsetofsleepduringactivities,insomecaseswithoutawarenessorwarning

signs,hasbeenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhiledriving

oroperatingmachinesduringtreatmentwithcabergoline.Patientswhohaveexperiencedsomnolenceand/oranepisode

ofsuddensleeponsetmustrefrainfromdrivingoroperatingmachines.Furthermoreareductionofdosageor

terminationoftherapymaybeconsidered.

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson’sdisease,includingcabergoline.

Other

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deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Precautions

Pharmacokineticinteractionswithothermedicinalproductscannotbepredictedbasedonavailableinformationabout

themetabolismofcabergoline.

NopharmacokineticinteractionwithL-Dopaorselegilinewasobservedinthestudiescarriedoutinparkinsonian

patients.

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.Itisnotknownwhetherthisoccursalsoinhumans.Dataona

limitednumberofpregnancies(n=100),generallytakenduringthefirst8weeksafterconception,donotindicate

cabergolinetobeassociatedwithanincreasedriskofabortion,prematuredelivery,multiplepregnancyorcongenital

abnormalities.Todate,nootherrelevantepidemiologicaldataareavailable.Animalstudiesindicatenodirector

indirectharmfuleffectswithrespecttopregnancy,embryonal/foetaldevelopment,parturitionorpost-natal

development.

Becauseofthelimitedexperienceoftheuseofcabergolineinpregnancy,cabergolineshouldbewithdrawnbeforea

plannedpregnancy.Ifthepatientbecomespregnantduringtreatment,cabergolineshallbeimmediatelywithdrawn.

Duringpregnancy,thesepatientsmustbecarefullymonitoredforanypregnancy-inducedpituitaryenlargement.

Cabergolineshouldonlybeusedduringpregnancyifclearlyindicated.

Cabergolinerestoresovulationandfertilityinwomenwithhyperprolactinaemichypogonadism:sincepregnancymight

occurpriortoreinitiationofmenses,pregnancytestingisrecommendedasappropriateduringtheamenorrhoeicperiod

and,oncemensesarereinitiated,everytimeamenstrualperiodisdelayedbymorethanthreedays.Womennotseeking

pregnancyshouldbeadvisedtouseeffectivenon-hormonalcontraceptionduringtreatmentandaftercabergoline

withdrawal.Becauseoflimitedexperienceonthesafetyoffoetalexposuretocabergoline,itisadvisablethatwomen

seekingpregnancyconceiveatleastonemonthaftercabergolinediscontinuationgiventhatovulatorycyclespersistin

somepatientsfor6monthsafterwithdrawal.Shouldpregnancyoccurduringtreatment,cabergolineistobe

discontinued.Asaprecautionarymeasure,womenwhobecomepregnantshouldbemonitoredtodetectsignsof

pituitaryenlargementsinceexpansionofpre-existingpituitarytumoursmayoccurduringgestation.

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Lactation

Cabergolineshouldnotbeadministeredtomotherswhoelecttobreastfeedtheirinfantssinceitpreventslactation.No

informationisavailableontheexcretionofactivesubstanceinmaternalmilkbutinratscabergolineand/orits

metabolitesareexcretedinthemilk.

Breastfeedingshouldbeavoidedwhentakingcabergoline.

4.7Effectsonabilitytodriveandusemachines

Cabergolinereducesbloodpressure,whichmayimpairthereactionsofcertainpatients.Thisshouldbetakeninto

accountinsituationsrequiringintenseawareness,suchaswhendrivingacaroroperatingmachinery.

Patientstreatedwithcabergolineandpresentingwithsomnolenceand/orsuddensleepepisodesmustbeinformedto

refrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesandothersatriskofserious

injuryordeath,untilsuchrecurrentepisodesandsomnolencehaveresolved(seesection4.4)

4.8Undesirableeffects

Post-marketingsurveillance

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.

Somnolence.Cabergolineisassociatedwithsomnolenceandhasbeenassociateduncommonlywithexcessivedaytime

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 Orthostatichypotension(mainlyevidentin

thefirstweeksoftherapy)

Cardiacvalvulopathy(including

regurgitation)andrelateddisorders

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Adjuvanttherapy

About1070parkinsonianpatientshavereceivedcabergolineasadjuvanttherapytoL-dopainclinicalstudies;ofthese

74%hadatleastoneadverseevent,mainlyofmildtomoderateseverityandtransientinnature,andrequiring

discontinuationinasmallproportionofcases.

Nervoussystemdisorders

Inthemajorityofcases(51%),eventswererelatedtothenervoussystem:mostfrequentlyreportedeventswere

Common

Uncommon 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

Notknown(cannotbeestimatedfrom

theavailabledata) Nausea

Vomiting,dyspepsia,gastritis,constipation.

Gastricupsetappearedmorefrequentin

femalethaninmalepatients.

Retroperitionealfibrosis

Skinandsubcutaneoustissue

disorders

Common Facialredness

Musculoskeletal,connectivetissue

andbonedisorders

Rare Crampinfingersandcalves

Vasculardisorders

Uncommon

Rare Nosebleeding

Fainting

Generaldisordersand

administrationsiteconditions

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Gastrointestinaldisorders

Thegastrointestinalsystemwasinvolvedin33%ofcases:eventsmostfrequentlyreportedwerenausea,vomiting,

dyspepsiaandgastritis.

Cardiacdisorders

Thecardiovascularsystemwasinvolvedin27%ofcases,mostfrequentlyreportedeventbeinghypotension.

Respiratory,thoracicandmediastinaldisorders

Therespiratorysystemwasinvolvedin13%ofcases,symptomaticpleuraleffusion/fibrosisbeingreportedwitha

frequency<2%.

4.9Overdose

Thereisnoclinicalexperienceofoverdosing,butobservationsfromanimalexperimentssuggestthatsymptoms

resultingfromoverstimulationofdopaminereceptorscanbeexpected,suchasnausea,vomiting,reducedblood

pressure,confusion/psychosisorhallucinations.Whereindicated,measuresmustbetakentorestorebloodpressure.In

addition,withpronouncedsymptomsfromtheCNS(hallucinations),administrationofadopamineantagonistcanbe

necessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiparkinsoniandrug,Dopamineagonist.

ATCCode:N04BC06

Cabergolineisasyntheticergotalkaloidandanergolinederivatewithlong-actingdopamineagonistandprolactin-

inhibitingproperties.AcentraldopaminergiceffectviaD2-receptorstimulationisachievedthroughhigherdosesthan

dosesthatreducethelevelsofserumprolactin.

ControlledclinicalstudieshavedemonstratedthatcabergolineiseffectiveinParkinson’sDiseaseatanaveragedoseof

4mg/dayfollowingtitration(upto5-6mgcabergoline/dayinthedifferentstudies).Cabergolinereducesdaily

fluctuationsinthemotorfunctioninpatientswithParkinson’sdiseasethatarebeingtreatedwithlevodopa/carbidopa.

Innewlydiagnosedpatients,cabergolineadministeredasmonotherapyhasbeenshowntoproducesomewhatless

frequentclinicalimprovementcomparedwithlevodopa/carbidopa.

Withregardtotheendocrineeffectsofcabergolinenotrelatedtotheantiprolactinaemiceffect,availabledatafrom

humansconfirmtheexperimentalfindingsinanimalsindicatingthatthetestcompoundisendowedwithavery

selectiveactionwithnoeffectonbasalsecretionofotherpituitaryhormonesorcortisol.

Thepharmacodynamicactionsofcabergolinenotcorrelatedwiththetherapeuticeffectonlyrelatetobloodpressure

decrease.Themaximalhypotensiveeffectofcabergolineassingledoseusuallyoccursduringthefirst6hoursafter

activesubstanceintakeandisdose-dependentbothintermsofmaximaldecreaseandfrequency.

5.2Pharmacokineticproperties

Absorption

Afteroraladministrationcabergolineisrapidlyabsorbedfromthegastrointestinaltractasthepeakplasma

concentrationisreachedwithin0.5to4hours.

Fooddoesnotappeartoaffectabsorptionanddispositionofcabergoline.

Distribution

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

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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

differenttoman.Preclinicalsafetystudiesofcabergolineindicatealargesafetymarginforthiscompoundinrodents

andinmonkeys,aswellasalackofteratogenic,mutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Leucine

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackagetoprotectfrommoisture.

6.5Natureandcontentsofcontainer

TypeIIIamberglassbottlewithapolypropylenescrewcap.

Acylindricaltubeorsachetcontainingdesiccant(silicagel)isprovidedineachbottle.

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Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

ArrowGenericsLimited,

Unit2,EastmanWay,

Stevenage,

Herts,

SG14SZ,U.K.

8MARKETINGAUTHORISATIONNUMBER

PA1130/010/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

February2008

10DATEOFREVISIONOFTHETEXT

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