CABASER 2 MG TABLET

Main information

  • Trade name:
  • CABASER 2 MG TABLET
  • Dosage:
  • 2 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CABASER 2 MG TABLET
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0936/044/002
  • Authorization date:
  • 29-10-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cabaser2mgTablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachTabletcontains2mgofCabergoline.

Eachtabletalsocontains150.8mgofanhydrouslactose.

Forfulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Tablet

White,oval,bothsidesconcavetablets,onesidescoredandengraved“7”ontheleftofthebreaklineand“02”onthe

rightofit.

Thetabletcanbedividedintoequalhalves

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofParkinson'sdisease

Iftreatmentwithadopamineagonistisbeingconsidered,Cabaserisindicatedassecondlinetherapyinpatientswho

areintolerantorfailtreatmentwithanon-ergotcompound,asmonotherapy,orasadjunctivetreatmenttolevodopaplus

dopa-decarboxylaseinhibitor,inthemanagementofthesignsandsymptomsofParkinson’sdisease.

Treatmentshouldbeinitiatedunderspecialistsupervision.Thebenefitofcontinuedtreatmentshouldberegularly

reassessedtakingintoaccounttheriskoffibroticreactionsandvalvulopathy(seesections4.3,4.4and4.8).

4.2Posologyandmethodofadministration

Cabaserisfororaladministration.Sincethetolerabilityofdopaminergicagentsisimprovedwhenadministeredwithfood,

itisrecommendedthatCabaserbetakenwithmeals.

Cabaserisintendedforchronic,longtermtreatment.

Adultsandelderlypatients

Asexpectedfordopamineagonists,doseresponseforbothefficacyandsideeffectsappearstobelinkedtoindividual

sensitivity.Optimizationofdoseshouldbeobtainedthroughslowinitialdosetitration,fromstartingdosesof1mgdaily.

Thedosageofconcurrentlevodopamaybegraduallydecreased,whilethedosageofCabaserisincreased,untilthe

optimumbalanceisdetermined.Inviewofthelonghalf-lifeofthecompound,incrementsofthedailydoseof0.5-1mg

shouldbedoneatweekly(initialweeks)orbi-weeklyintervals,uptooptimaldoses.

Therecommendedtherapeuticdosageis2to3mg/dayforpatientswithsignsandsymptomsofParkinson'sdisease.

Cabasershouldbegivenasasingledailydose.

Useinchildren

ThesafetyandefficacyofCabaserhavenotbeeninvestigatedinchildrenasParkinson'sdiseasedoesnotaffectthis

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 1

4.3Contraindications

HypersensitivitytoCabaser,anyexcipientoftheproduct,oranyergotalkaloids.

Historyofpulmonary,pericardialandretroperitonealfibroticdisorders.

Forlong-termtreatment:Evidenceofcardiacvalvulopathyasdeterminedbypre-treatmentechocardiography.

(Seesection4.4Specialwarningsandprecautionsforuse–Fibrosisandcardiacvalvulopathyandpossiblyrelated

clinicalphenomena)

4.4Specialwarningsandprecautionsforuse

General:

Aswithotherergotderivatives,CabaserRshouldbegivenwithcautiontopatientswithseverecardiovasculardisease,

Raynaud'ssyndrome,pepticulcerorgastrointestinalbleeding,orwithahistoryofserious,particularlypsychotic,

mentaldisorders.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

RenalInsufficiency:NooveralldifferencesinthepharmacokineticsofCabaserwereobservedin12patientshaving

moderate(creatinineclearance31-60ml/min)tosevere(creatinineclearance8-26ml/min)renaldisease.The

pharmacokineticsofCabaserinthesepatientsweresimilartothoseofhealthyvolunteersasexpected,sinceonlyasmall

fractionofCabaseriseliminatedrenally.ThepharmacokineticsofCabaserhasnotbeenstudiedinpatientshavingend-

stagerenalfailure,orinpatientsonhaemodialysis;thesepatientsshouldbetreatedwithcaution.

HepaticInsufficiency:

LowerdosesofCabasershouldbeconsideredinpatientswithseverehepaticinsufficiency.Comparedtonormal

volunteersandthosewithlesserdegreesofhepaticinsufficiency,anincreaseinAUChasbeenseeninpatientswith

severehepaticinsufficiency(Child-PughClassC)whoreceivedasingle1mgdose.

PosturalHypotension:

PosturalhypotensioncanoccurfollowingadministrationofCabaser,particularlyduringthefirstdaysofadministration

ofCabaser.CareshouldbeexercisedwhenadministeringCabaserconcomitantlywithotherdrugsknowntolower

bloodpressure.

Fibrosisandcardiacvalvulopathyandpossiblyrelatedclinicalphenomena:

Fibroticandserosalinflammatorydisorderssuchaspleuritis,pleuraleffusion,pleuralfibrosis,pulmonaryfibrosis,

pericarditis,pericardialeffusion,cardiacvalvulopathyinvolvingoneormorevalves(aortic,mitralandtricuspid)or

retroperitonealfibrosishaveoccurredafterprolongedusageofergotderivativeswithagonistactivityattheserotonin

receptor,suchasCabaser.Therefore,Cabasershouldbegivenwithcautiontopatientswithahistoryorclinical

symptomsofcardiacdisorderslinkedtofibrotictissuedegeneration.

Insomecases,symptomsormanifestationsofcardiacvalvulopathyimprovedafterdiscontinuationofCabaser.

Erythrocytesedimentationrate(ESR)hasbeenfoundtobeabnormallyincreasedinassociationwithpleural

effusion/fibrosis.Chestx-rayexaminationisrecommendedincasesofunexplainedESRincreasestoabnormalvalues.

Serumcreatininemeasurementscanalsobeusedtohelpinthediagnosisoffibroticdisorder.Followingdiagnosisof

pleuraleffusion/pulmonaryfibrosisorvalvulopathy,thediscontinuanceofCabaserhasbeenreportedtoresultin

improvementofsignsandsymptoms.(Seesection4.3Contraindications)

Valvulopathyhasbeenassociatedwithcumulativedoses,thereforepatientsshouldbetreatedwiththelowesteffective

dose.Ateachvisit,theriskbenefitprofileofCabasertreatmentforthepatientshouldbereassessedtodeterminethe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 2

Beforeinitiatinglong-termtreatment:

Allpatientsmustundergoacardiovascularevaluation,includingechocardiogram,toassessthepotentialpresenceof

asymptomaticvalvulardisease.Itisalsoappropriatetoperformbaselineinvestigationsoferythrocytesedimentation

rateorotherinflammatorymarkers,lungfunction/chestx-rayandrenalfunctionpriortoinitiationoftherapy.In

patientswithvalvularregurgitation,itisnotknownwhetherCabasertreatmentmightworsentheunderlyingdisease.If

fibroticvalvulardiseaseisdetected,thepatientshouldnotbetreatedwithCabaser(seeSection4.3Contraindications).

Duringlong-termtreatment:

Fibroticdisorderscanhaveaninsidiousonsetandpatientsshouldberegularlymonitoredforpossiblemanifestationsof

progressivefibrosis.Thereforeduringtreatment,attentionshouldbepaidtothesignsandsymptomsof:

Pleuro-pulmonarydisease,suchasdyspnoea,shortnessofbreath,persistentcough,orchestpain.

Renalinsufficiencyorureteral/abdominalvascularobstructionthatmayoccurwithpainintheloin/flank,andlower

limboedema,aswellasanypossibleabdominalmassesortendernessthatmayindicateretroperitonealfibrosis.

Cardiacfailure:casesofvalvularandpericardialfibrosishaveoftenmanifestedascardiacfailure.Therefore,

valvularfibrosis(andconstrictivepericarditis)shouldbeexcludedifsuchsymptomsoccur.

Clinicaldiagnosticmonitoringfordevelopmentoffibroticdisorders,asappropriate,isessential.Followingtreatment

initiation,thefirstechocardiogramshouldoccurwithin3-6months;thereafter,thefrequencyofechocardiographic

monitoringshouldbedeterminedbyappropriateindividualclinicalassessmentwithparticularemphasisontheabove-

mentionedsignsandsymptoms,butmustoccuratleastevery6to12months.

Cabasershouldbediscontinuedifanechocardiogramrevealsneworworsenedvalvularregurgitation,valvular

restrictionorvalveleafletthickening.(SeeSection4.3Contraindications)

Theneedforotherclinicalmonitoring(e.g.,physicalexaminationincluding,cardiacauscultation,X-ray,CTscan)

shouldbedeterminedonanindividualbasis.

Additionalappropriateinvestigationssuchaserythrocytesedimentationrate,andserumcreatininemeasurements

shouldbeperformedifnecessarytosupportadiagnosisofafibroticdisorder.

SymptomatichypotensioncanoccurfollowingadministrationofCabaser:particularattentionshouldbepaidwhen

administeringCabaserconcomitantlywithotherdrugsknowntolowerbloodpressure.Becauseofitseliminationhalf-

lifehypotensiveeffectsmaypersistforafewdaysaftercessationoftherapy.

Somnolence/SuddenSleepOnset:

Cabaserhasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,inpatientswithParkinson'sdisease.

Suddenonsetofsleepduringdailyactivities,insomecaseswithoutawarenessorwarningsigns,hasbeenreported.

Patientsmustbeinformedofthisandadvisedtoexercisecautionwhiledrivingoroperatingmachinesduringtreatment

withCabaser.Patientswhohaveexperiencedsomnolenceand/oranepisodeofsuddensleeponsetmustrefrainfrom

drivingoroperatingmachines.Furthermoreareductionindosageorterminationoftherapymaybeconsidered.(See

section4.7Effectsonabilitytodriveandusemachines)

Psychiatric:

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamineagonists

includingCabaser.Thishasbeengenerallyreversibleuponreductionofthedoseortreatmentdiscontinuation

TheeffectsofalcoholonoveralltolerabilityofCabaserarecurrentlyunknown.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Theconcomitantuseofantiparkinsonnon-dopamineagonists(e.g.selegiline,amantadine,biperiden,trihexyphenidyl)

wasallowedinclinicalstudiesforpatientsreceivingCabaser.Instudieswherethepharmacokineticinteractionsof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 3

NoinformationisavailableaboutinteractionbetweenCabaserandotherergotalkaloids:thereforetheconcomitantuseof

thesemedicationsduringlong-termtreatmentwithCabaserisnotrecommended.

SinceCabaserexertsitstherapeuticeffectbydirectstimulationofdopaminereceptors,itshouldnotbeconcurrently

administeredwithdrugswhichhavedopamine-antagonistactivity(suchasphenothiazines,butyrophenones,thioxanthenes,

metoclopramide)sincethesemightreducethetherapeuticeffectofCabaser.

Aswithotherergotderivatives,Cabasershouldnotbeusedinassociationwithmacrolideantibiotics(e.g.erythromycin)

duetoincreasedsystemicbioavailability.

4.6Fertility,pregnancyandlactation

Inatwelveyearobservationalstudyonpregnancyoutcomesfollowingcabergolinetherapy,informationisavailableon

256pregnancies.Seventeenofthese256pregnancies(6.6%)eventuatedinmajorcongenitalmalformationsor

abortion.Informationisavailableon23/258infantswhohadatotalof27neonatalabnormalities,bothmajorand

minor.Musculoskeletalmalformationswerethemostcommonneonatalabnormality(10),followedbycardio-

pulmonaryabnormalities(5).Thereisnoinformationonperinataldisordersorlong-termdevelopmentofinfants

exposedtointra-uterinecabergoline.Basedonrecentpublishedliterature,theprevalenceofmajorcongenital

malformationsinthegeneralpopulationhasbeenreportedtobe6.9%orgreater.Ratesofcongenitalabnormalityvary

betweendifferentpopulations.Itisnotpossibletoaccuratelydetermineifthereisanincreasedriskasnocontrolgroup

wasincluded.

ItisrecommendedthatcontraceptionisusedwhilstontreatmentwithCabaser.

InratsCabaserand/oritsmetabolitesareexcretedinmilk.Noinformationisavailableonexcretioninbreastmilkin

humans;however,lactationisexpectedtobeinhibited/suppressedbyCabaser,inviewofitsdopamine-agonistproperties.

Mothersshouldbeadvisednottobreast-feedwhilebeingtreatedwithCabaser.

4.7Effectsonabilitytodriveandusemachines

PatientsbeingtreatedwithCABASERandpresentingwithsomnolenceand/orsuddensleeponsetepisodesmustbe

informedtorefrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersatriskof

seriousinjuryordeath(eg,operatingmachines)untilsuchepisodesandsomnolencehaveresolved(Seesection4.4Special

warningsandprecautionsforuse–Somnolence/SuddenSleepOnset).

4.8Undesirableeffects

ThefollowingundesirableeffectshavebeenobservedandreportedduringtreatmentwithCabaserwiththefollowing

frequencies:Verycommon(1/10);common(1/100to<1/10);uncommon(1/1,000to1/100);rare(1/10,000to

1/1,000);veryrare(1/10,000),notknown(cannotbeestimatedfromtheavailabledata).

NewlyDiagnosedParkinson’sPatients

MedDRA

SystemOrganClass Frequency UndesirableEffects

Psychiatricdisorders Common Hallucinations,sleepdisturbances

Nervoussystemdisorders Common Dizziness,dyskinesias

Vasculardisorders Common Posturalhypotension

Gastrointestinaldisorders

Verycommon Nausea

Common Constipation,dyspepsia,gastritis,

vomiting

Generaldisordersand

administrationsite

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 4

PatientsonAdjunctLevodopaTherapy

MedDRA

SystemOrganClass Frequency UndesirableEffects

Psychiatricdisorders Common Confusion,hallucinations

Nervoussystemdisorders Common Dizziness,dyskinesia

Uncommon Hyperkinesia

Cardiacdisorders Common Angina

Vasculardisorders Common Posturalhypotension

Uncommon Erythromelalgia

Respiratory,thoracicand

mediastinaldisorders Uncommon Pleuraleffusion,pulmonaryfibrosis

Gastrointestinaldisorders Verycommon Nausea

Common Dyspepsia,gastritis,vomiting

Generaldisordersand

administrationsite

conditions Common Peripheraledema

Investigations Common Decreasedhemoglobin,hematocrit,

and/orredbloodcell(>15%vs

baseline)

Post-marketingSurveillance

MedDRA

SystemOrganClass Frequency UndesirableEffects

Immunesystemdisorders Uncommon Hypersensitivityreaction

Psychiatricdisorders Common Increasedlibido

Uncommon Delusions,psychoticdisorder

NotKnown Aggression,hypersexuality,

pathologicalgambling

Nervoussystemdisorders Common Headache,somnolence

NotKnown Suddensleeponset,syncope

Cardiacdisorders VeryCommon Valvulopathy(includingregurgitation)

andrelateddisorders(pericarditisand

pericardialeffusion)

Vasculardisorders NotKnown Digitalvasospasm

Respiratory,thoracicand

mediastinaldisorders Common Dyspnea

Veryrare Fibrosis

NotKnown Respiratorydisorder,respiratory

failure

Hepato-biliarydisorders Uncommon Hepaticfunctionabnormal

Skinandsubcutaneous

tissuedisorders Uncommon Rash

NotKnown Alopecia

Musculoskeletaland

connectivetissuedisorders NotKnown Legcramps

Generaldisordersand

administrationsite

conditions Common Asthenia

Uncommon Edema,fatigue

Investigations Common Liverfunctiontestsabnormal

NotKnown Bloodcreatininephosphokinase

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 5

4.9Overdose

Symptomsofoverdosewouldlikelybethoseofover-stimulationofdopaminereceptorse.g.nausea,vomiting,gastric

complaints,posturalhypotension,confusion/psychosisorhallucinations.

Supportivemeasuresshouldbetakentoremoveunabsorbeddrugandtomaintainbloodpressure,ifnecessary.In

addition,theadministrationofdopamineantagonistdrugsmaybeadvisable.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Cabaserisadopaminergicergolinederivativeendowedwithpotentandlong-lastingdopamineD2receptoragonist

properties.

CabaserhasshowedtobeeffectiveindecreasingdailyfluctuationsinmotorperformanceinParkinsonianpatients

receivinglevodopa/carbidopatherapy.Improvementofmotordeficithasbeendemonstrated,whilesubstantiallydecreasing

thelevodopa/carbidopadose.

InhealthyvolunteerstheadministrationofCabaseratsingleoraldosesof0.3-2.5mgwasassociatedwithasignificant

decreaseinserumPRLlevels.Theeffectisprompt(within3hoursofadministration)andpersistent(upto7-28days).

ThePRL-loweringeffectisdose-relatedbothintermsofdegreeofeffectanddurationofaction.

ThepharmacodynamicactionsofCabasernotlinkedtothetherapeuticeffectrelateonlytobloodpressuredecrease.The

maximalhypotensiveeffectofCabaserasasingledoseusuallyoccursduringthefirst6hoursafterdrugintakeandisdose-

dependentbothintermsofmaximaldecreaseandfrequency.

5.2Pharmacokineticproperties

ThepharmacokineticandmetabolicprofilesofCabaserhavebeenstudiedinhealthyvolunteersofbothsexes,infemale

hyperprolactinemicpatientsandinparkinsonianpatients.Afteroraladministrationofthelabelledcompound,radioactivity

wasrapidlyabsorbedfromthegastrointestinaltractasthepeakofradioactivityinplasmawasbetween0.5and4hours.

Tendaysafteradministrationabout18/20%and55/72%oftheradioactivedose( 3

H-cabergoline/ 14

C-cabergoline)was

recoveredinurineandfaeces,respectively.Unchangeddruginurineaccountedfor2-3%ofthedose.

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

additionalmetaboliteswereidentifiedinurine,whichaccountedoverallforlessthan3%ofthedose.Themetaboliteshave

beenfoundtobemuchlesspotentthanCabaserasD

dopaminereceptoragonists"invitro".

ThelowurinaryexcretionofunchangedCabaserhasbeenconfirmedalsoinstudieswithnon-radioactiveproduct.The

eliminationhalf-lifeofCabaser,estimatedfromurinaryexcretionrates,islong(63-68hoursinhealthyvolunteers,79-115

hoursinhyperprolactinemicpatients).

ThepharmacokineticsofCabaserseemtobedose-independentbothinhealthyvolunteers(dosesof0.5-1.5mg)and

parkinsonianpatients(steadystateofdailydosesupto7mg/day).

Onthebasisoftheeliminationhalf-life,steadystateconditionsshouldbeachievedafter4weeks,asconfirmedbythe

meanpeakplasmalevelsofCabaserobtainedafterasingledose(37+8pg/ml)andaftera4weekmultiple-regimen

(101+43pg/ml)."Invitro"experimentsshowedthatthedrugatconcentrationsof0.1-10ng/mlis41-42%boundtoplasma

proteins.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 6

WhilerenalinsufficiencyhasbeenshownnottomodifyCabaserkinetics,hepaticinsufficiencyofseveredegree(>10

Child-Pughscore,maximumscore12)hasbeenshowntobeassociatedwithanincreaseofAUC.

5.3Preclinicalsafetydata

Almostallthefindingsnotedthroughouttheseriesofpreclinicalsafetystudiesareaconsequenceofthecentral

dopaminergiceffectsorthelong-lastinginhibitionofPRLinrodentswithaspecifichormonalphysiologydifferentto

man.

PreclinicalsafetystudiesofCabaserindicateaconsistentsafetymarginforthiscompoundinrodentsandinmonkeys,as

wellasalackofteratogenic,genotoxicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactoseanhydrous

Leucine

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

C.Containersshouldbekepttightlyclosedinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Amberglassbottleswithaluminiumtamperresistantscrewcapequippedwithalowdensitypolyethylene/

thermoplasticelastomerplasticundercapactingasacontainerholdingsilicagel,closedbyaplasticcupwithporous

paperatthelowerextremity.

Eachbottlecontains20or30tabletsandisenclosedinanoutercardboardbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Bottlesofcabaseraresuppliedwithdesiccantinthecaps.Thisdesiccantmustnotberemoved.

7MARKETINGAUTHORISATIONHOLDER

PharmaciaIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 7

8MARKETINGAUTHORISATIONNUMBER

PA936/44/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29October1999

Dateoflastrenewal:29October2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/10/2011 CRN 2107064 page number: 8