DALZIOR

Main information

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

Documents

Localization

  • Available in:
  • DALZIOR Tablets 0.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0436/045/001
  • Authorization date:
  • 29-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dalzior0.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains0.5mgcabergoline.

Excipient:lactose75.8mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

White,oval-shaped,flat,bevelledtabletscontaining0.5mgcabergoline.Eachtabletisscoredononesideandhas

‘CBG’ononesideand‘0.5’ontheothersideofthebreakline.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inhibitionoflactationformedicalreasons.

Hyperprolactimaemicdisorders

Prolactinsecretingpituitaryadenomas

Idiopathichyperprolactinaemia

Itisrecommendedthatthemedicinalproductisinitiallyprescribedbyanappropriatespecialistorafterconsultinga

specialist.

4.2Posologyandmethodofadministration

Cabergolineistobeadministeredbytheoralroute.

Inordertoreducetheriskofgastrointestinalundesirableeffectsitisrecommendedthatcabergolineistakenwithmeals

foralltherapeuticindications.

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Adults:

Treatmentofhyperprolactinaemicdisorders:

Therecommendedinitialdosageis0.5mgcabergolineperweekgiveninoneortwodoses(e.g.onMondayand

Thursday)perweek.Theweeklydoseshouldbeincreasedgradually,preferablybyadding0.5mgcabergolineper

weekatmonthlyintervalsuntilanoptimaltherapeuticresponseisachieved.

Thetherapeuticdosageisusually1mgcabergolineperweekandrangesfrom0.25mgto2mgcabergolineperweek.

Dosesofupto4.5mgcabergolineperweekhavebeenusedinhyperprolactinaemicpatients.

Theweeklydosemaybegivenasasingleadministrationordividedintotwoormoredosesperweekaccordingto

patienttolerability.Divisionoftheweeklydoseintomultipleadministrationsisadvisedwhendoseshigherthan1mg

cabergolineperweekaretobegivensincethetolerabilityofdosesgreaterthan1mgcabergolinetakenasasingle

weeklydosehasbeenevaluatedonlyinafewpatients.

Patientsshouldbeevaluatedduringdoseescalationtodeterminethelowestdosagethatproducesthetherapeutic

response.

Forinhibitionoflactation:

Cabergolineshouldbeadministeredwithinthefirst24hourspost-partum.Therecommendedtherapeuticdosageis1

mgcabergolinegivenasasingledose.

Useinpatientswithhepaticorrenaldysfunction.

Useinpatientswithhepaticinsufficiencyandrenalinsufficiencyseesections4.3and4.4

Useinchildrenandadolescents:

Thesafetyandefficacyofcabergolinehasnotbeenestablishedinsubjectslessthan16yearsofage.

Useintheelderly:

Asaconsequenceoftheindicationsforwhichcabergolineispresentlyproposed,theexperienceintheelderlyisvery

limited.Availabledatadonotindicateaspecialrisk.

4.3Contraindications

Pre-eclampsia,eclampsia

Post-partumhypertensionoruncontrolledhypertension.

Hypersensitivitytocabergoline,otherergotalkaloidsortoanyoftheexcipients.

Severeimpairmentofliverfunction

Historyofadversepulmonaryreactions,suchaspleuritisandfibrosis,associatedwithuseofdopamineagonists.

Historyofpsychosisorriskofpost-partumpsychosis

Forlong-termtreatment:anatomicalevidenceofcardiacvalvulopathyasdeterminedbypre-treatment

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4.4Specialwarningsandprecautionsforuse

General:

Theassessmentofsafetyandefficacyofcabergolineislimitedinpatientswithrenalandhepaticdisease.Aswithother

ergotalkaloids,cabergolineshouldbegivenwithcautiontosubjectswithcardiovasculardisease,hypotension,

Raynaud'ssyndrome,pepticulcerorgastrointestinalbleeding.Theeffectsofalcoholonoveralltolerabilityof

cabergolinearecurrentlyunknown.

Treatmentofhyperprolactinaemia:

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-treatment:

Allpatientsshouldundergoacardiovascularevaluation,includingechocardiogram,toassessthepotentialpresenceof

asymptomaticvalvulardisease.Itisalsoappropriatetoperformbaselineinvestigationsoferythrocytesedimentation

rateorotherinflammatorymarkers,lungfunction/chestx-rayandrenalfunctionpriortoinitiationoftherapy.

Inpatientswithvalvularregurgitation,itisnotknownwhethercabergolinetreatmentmightworsentheunderlying

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

Duringlong-termtreatment:

Fibroticdisorderscanhaveaninsidiousonsetandpatientsshouldberegularlymonitoredforpossiblemanifestationsof

progressivefibrosis.

Thereforeduringtreatment,attentionshouldbepaidtothesignsandsymptomsof:

Pleuropulmonarydisease,suchasdyspnoea,shortnessofbreath,persistentcough,orchestpain.

Renalinsufficiencyorureteral/abdominalvascularobstructionthatmayoccurwithpainintheloin/flank,andlower

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Cardiacfailurecasesofvalvularandpericardialfibrosishaveoftenmanifestedascardiacfailure.Therefore,valvular

fibrosis(andconstrictivepericarditis)shouldbeexcludedifsuchsymptomsoccur.

Clinicaldiagnosticmonitoringfordevelopmentoffibroticdisorders,asappropriate,isessential.Followingtreatment

initiation,thefirstechocardiogrammustoccurwithin3-6months,thereafter,thefrequencyofechocardiographic

monitoringshouldbedeterminedbyappropriateindividualclinicalassessmentwithparticularemphasisontheabove-

mentionedsignsandsymptoms,butmustoccuratleastevery6to12months.

Cabergolineshouldbediscontinuedifanechocardiogramrevealsneworworsenedvalvularregurgitation,valvular

restrictionorvalveleafletthickening.(SeeSection4.3)

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

shouldbedeterminedonanindividualbasis.

Additionalappropriateinvestigationssuchaserythrocytesedimentationrate,andserumcreatininemeasurements

shouldbeperformedifnecessarytosupportadiagnosisoffibroticdisorder.

Hypotension:

Symptomatichypotensioncanoccurwithin6hoursfollowingadministrationofcabergoline:particularattentionshould

bepaidwhenadministeringcabergolineconcomitantlywithothermedicicalproductknowntolowerbloodpressure.

Becauseofitseliminationhalf-lifehypotensiveeffectsmaypersistforafewdaysaftercessationoftherapy.

Monitoringoftreatmentwithregularchecksofbloodpressureisrecommendedinthefirst3-4daysafterinitiationof

treatment.

Lowbloodpressure( ≥20mmHgsystolicand≥10mmHgdiastolic)hasbeenreportedinthe3-4daysfollowinga

singledoseof1mgcabergolineinpost-partumstudies.Theundesirableeffectsgenerallyoccurinthefirsttwoweeks,

andthendeclineordisappear.3%ofthepatientshadtheirtreatmentdiscontinuedonaccountoftheundesirableeffects.

Somnolence

Cabergolinehasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,particularlyinpatientswith

Parkinson’sdisease.Suddenonsetofsleepduringdailyactivities,insomecaseswithoutawarenessorwarningsigns,

hasbeenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhiledrivingor

operatingmachinesduringtreatmentwithcabergoline.

Patientswhohaveexperiencedsomnolenceand/oranepisodeofsuddensleeponsetmustrefrainfromdrivingor

operatingmachinesduringtreatmentwithcabergoline(seesection4.7).Furthermore,areductionofdosageor

terminationoftreatmentmaybeconsidered.

RenalInsufficiency:Nooveralldifferencesinthepharmacokineticsofcabergolinewereobservedinmoderatetosevere

renaldisease.Thepharmacokineticsofcabergolinehasnotbeenstudiedinpatientshavingend-stagerenalfailure,orin

patientsonhaemodialysis;thesepatientsshouldbetreatedwithcaution.

Other

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Pathologicgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamineagonists

forParkinson’sdisease,includingcabergoline.

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Becauseclinicalexperienceisstilllimitedandtheproducthasalonghalf-life,asaprecautionarymeasureitis

recommendedthat onceregularovulatorycycleshavebeenachievedwomenseekingpregnancyshould

discontinueDalzior0.5mgTabletsonemonthbeforeintendedconception.

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.

4.6Fertility,pregnancyandlactation

Pregnancy

Beforecabergolineadministration,pregnancyshouldbeexcludedandaftertreatmentpregnancyshouldbeprevented

foratleastonemonth.

Cabergolinehasbeenshowntocrosstheplacentainrats.Itisnotknownwhetherthisoccursinhumans.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.

Contraceptionshouldbecontinuedforatleast4weeksafterstoppingcabergoline.

Cabergolinerestoresovulationandfertilityinwomenwithhyperprolactinaemichypogonadism:sincepregnancymight

occurpriortoreinitiationofmenses,pregnancytestingisrecommendedasappropriateduringtheamenorrhoeicperiod

and,oncemensesarereinitiated,everytimeamenstrualperiodisdelayedbymorethanthreedays.Womennotseeking

pregnancyshouldbeadvisedtouseeffectivenon-hormonalcontraceptionduringtreatmentandaftercabergoline

withdrawal.Becauseoflimitedexperienceonthesafetyoffoetalexposuretocabergoline,itisadvisablethatwomen

seekingpregnancyconceiveatleastonemonthaftercabergolinediscontinuationgiventhatovulatorycyclespersistin

somepatientsfor6monthsafterwithdrawal.Shouldpregnancyoccurduringtreatment,cabergolineistobe

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Asaprecautionarymeasure,womenwhobecomepregnantshouldbemonitoredtodetectsignsofpituitary

enlargementsinceexpansionofpre-existingpituitarytumoursmayoccurduringgestation.

Cabergolineshouldonlybeusedduringpregnancyifclearlyindicated.

Lactation

Cabergolineshouldnotbeadministeredtomotherswhoelecttobreastfeedtheirinfantssinceitpreventslactation.No

informationisavailableontheexcretionoftheactivesubstanceinmaternalmilkbutinratscabergolineand/orits

metabolitesareexcretedinthemilk.

Lactationshouldbeavoidedwhentakingcabergoline.

4.7Effectsonabilitytodriveandusemachines

Cabergolinereducesbloodpressure,whichmayimpairthereactionsofcertainpatients.Thisshouldbetakeninto

accountinsituationsrequiringintenseawareness,suchaswhendrivingacaroroperatingmachinery.

Patientstreatedwithcabergolineandpresentingwithsomnolenceand/orsuddensleepepisodesmustbeinformedto

refrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersatriskofserious

injuryordeath,untilsuchrecurrentepisodesandsomnolencehaveresolved(seesection4.4).

4.8Undesirableeffects

Theundesirableeffectsareusuallydose-dependent,andcanbereducedbydecreasingthedosegradually.

Inhibitionoflactation:Approximately14%ofthepatientsexperienceundesirableeffects.Themostcommonarelow

bloodpressure(12%),dizziness(6%)andheadaches(5%).Long-termtreatmentincreasesthefrequencyofundesirable

effectstoapproximately70%.

Thefollowingconventionhasbeenutilisedfortheclassificationofundesirableeffects:

Verycommon( ≥1/10),

Common( ≥1/100to<1/10),

Uncommon( ≥1/1000to<1/100),

Rare( ≥1/10,000to<1/1000),

Veryrare(<1/10,000).

Cardiacdisorders

VeryCommon:Cardiacvalvulopathy(includingregurgitation)andrelateddisorders(pericarditisandpericardial

effusion)

Common:lowbloodpressure,palpitationsandchestpain

NervousSystemDisorders

Common:depression,headachesanddizziness,paresthesia,fatigue,somnolence

EyeDisorders

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Gastrointestinaldisorders

Common:Nausea,vomiting,gastricpains,gastritis,constipation,dyspepsia

Skinandsubcutaneoustissuedisorders

Common:facialredness

Musculoskeletalandconnectivetissuedisorders

Rare:Crampinfingersandcalves.

VascularDisorders

Uncommon:Nosebleeding.

Rare:Fainting

Post-marketingSurveillance:

Cabergolineisassociatedwithsomnolenceandhasbeenassociateduncommonlywithexcessivedaytimesomnolence

andsuddensleeponsetepisodes.

PatientstreatedwithdopamineagonistsfortreatmentofParkinson’sdisease,includingcabergoline,especiallyathigh

doses,havebeenreportedasshowingpathologicalgambling,increasedlibidoandhypersexuality,generallyreversible

uponreductionofthedoseortreatmentdiscontinuation.

Thefollowingeventshavebeenreportedinassociationwithcabergoline:

Fibrosis(seesection4.4).

Hallucinations

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

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

effectmeansthatasingledoseisgenerallysufficienttostoptheinitiationofmilksecretion.Intreatmentof

hyperprolactinaemia,theserumprolactinlevelsaregenerallynormalisedwithintwotofourweeksoftheoptimaldose

beingattained.Prolactincanstillbesignificantlyreducedseveralmonthsafterwithdrawalofthetreatment.

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)for0.5mgcabergolinedose.

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

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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