EIRONIL

Main information

  • Trade name:
  • EIRONIL Film Coated Tablet 2.0 Milligram
  • Dosage:
  • 2.0 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EIRONIL Film Coated Tablet 2.0 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/032/004
  • Authorization date:
  • 12-12-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0585/032/004

CaseNo:2039486

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PlivaPharmaLimited

VisionHouse,BedfordRoad,Petersfield,HampshireGU323QB,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Eironil2mgfilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom12/12/2008until11/12/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 17/12/2008 CRN 2039486 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Eironil2mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each2mgfilm-coatedtabletcontains2.0mgofropinirole(ashydrochloride).

Excipient(s):

Each2mgfilm-coatedtabletcontains62.083mgoflactose(asmonohydrate)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablet

Whiteroundbiconvexfilmcoatedtabletdebossedwith'RO'ononesideand'2'ontheotherside

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofParkinson'sdiseaseunderthefollowingconditions:

Initialtreatmentasmonotherapy,inordertodelaytheintroductionoflevodopa.

Incombinationwithlevodopa,overthecourseofthedisease,whentheeffectoflevodopawearsofforbecomes

inconsistentandfluctuationsinthetherapeuticeffectoccur("endofdose"or"on-off"typefluctuations).

RopiniroleisalsoindicatedforthesymptomatictreatmentofmoderatetosevereidiopathicRestlessLegsSyndrome

(seesection5.1).

4.2Posologyandmethodofadministration

Oraluse.

Thetabletsshouldbeswallowedwholewithfluidandpreferablytakenwithmeals.

Differentstrengthsofthismedicinalproductareavailableinordertoallowdosingaccordingtotherecommended

treatmentinitiationandtherapeuticregimensbelow.Whentheavailablerangeofstrengthsdoesnotpermitdose

titrationaccordingtothetreatmentinitiationregimen,Ropiniroleshouldnotbeusedinropinirolenaïvepatients.

TreatmentofidiopathicParkinson'sDisease:

Adults

Individualdosetitrationagainstefficacyandtolerabilityisrecommended.Ropiniroleshouldbetakenthreetimesaday

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Treatmentinitiation:Theinitialdoseshouldbe0.25mgt.i.d.Aguideforthetitrationregimenforthefirstfourweeks

oftreatmentisgiveninthetablebelow:

Therapeuticregimen:Aftertheinitialtitration,weeklyincrementsofupto3mg/daymaybegiven.Ropiniroleis

usuallygivenindivideddosesthreetimesperday.

Theproposedtitrationregimeisasfollows:

Atherapeuticresponsemaybeseenbetween3and9mg/day,althoughadjuncttherapypatientsmayrequirehigher

doses.Ifsufficientsymptomaticcontrolisnotachieved,ormaintained,thedoseofropinirolemaybeincreaseduntilan

acceptabletherapeuticresponseisestablished.Dosesabove24mg/dayhavenotbeeninvestigatedinclinicaltrialsand

thisdoseshouldnotbeexceeded.

Iftreatmentisinterruptedforonedayormorere-initiationbydosetitrationshouldbeconsidered(seeabove).

Whenropiniroleisadministeredasadjuncttherapytolevodopa,theconcurrentdoseoflevodopamaybereduced

graduallybyaround20%intotal.

Whenswitchingtreatmentfromanotherdopamineagonisttoropinirole,themanufacturer'sguidanceondiscontinuation

shouldbefollowedbeforeinitiatingropinirole.

Ropiniroleshouldbediscontinuedgraduallybyreducingthenumberofdailydosesovertheperiodofoneweek.

Renalimpairment:Inparkinsonianpatientswithmildtomoderaterenalimpairment(creatinineclearance30-50

ml/min)nochangeintheclearanceofropinirolewasobserved,indicatingthatnodosageadjustmentisnecessaryinthis

population.

Elderly:Theclearanceofropiniroleisdecreasedinpatientsover65yearsofage,butthedoseofropiniroleforelderly

patientscanbetitratedinthenormalmanner.

Childrenandadolescents:Parkinson'sdiseasedoesnotoccurinchildrenandadolescents.Theuseofropiniroleinthis

populationhasthereforenotbeenstudiedanditshouldnotbegiventochildren.

SymptomatictreatmentofmoderatetosevereidiopathicRestlessLegsSyndrome.

Adults

Individualdosetitrationagainstefficacyandtolerabilityisrecommended.Ropiniroleshouldbetakenjustbeforebed

time,howeverthedosecanbetakenupto3hoursbeforeretiring.Ropinirolemaybetakenwithfood,toimprove

gastrointestinaltolerance.

Treatmentinitiation(week1)

Therecommendedinitialdoseis0.25mgoncedaily(administeredasabove)for2days.Ifthisdoseiswelltolerated

thedoseshouldbeincreasedto0.5mgoncedailyfortheremainderofweek1.

Therapeuticregimen(week2onwards)

Followingtreatmentinitiation,thedailydoseshouldbeincreaseduntiloptimaltherapeuticresponseisachieved.The

Ripinirole Week1 Week2 Week3 Week4

Unitdose(mg) 0.25 0.5 0.75 1.0

TotalDailydose(mg) 0.75 1.5 2.25 3.0

Ripinirole Week5 Week6 Week7 Week8

Unitdose(mg) 1.5 2.0 2.5 3.0

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Thedosemaybeincreasedto1mgonceadayatweek2.Thedosemaythenbeincreasedby0.5mgperweekoverthe

nexttwoweekstoadoseof2mgonceaday.Insomepatients,toachieveoptimalimprovement,thedosemaybe

increasedgraduallyuptoamaximumof4mgonceaday.Inclinicaltrialsthedosewasincreasedby0.5mgeachweek

to3mgonceadayandthenby1mguptothemaximumrecommendeddoseof4mgonceadayasshowninthetable

below.

Dosesabove4mgoncedailyhavenotbeeninvestigatedinRestlessLegsSyndromepatients.

Dosetitration

*Toachieveoptimalimprovementinsomepatients

Thepatient’sresponsetoropiniroleshouldbeevaluatedafter3monthstreatment(seesection5.1).Atthistimethe

doseprescribedandtheneedforcontinuedtreatmentshouldbeconsidered.Iftreatmentisinterruptedformorethana

fewdaysitshouldbere-initiatedbydosetitrationcarriedoutasabove.

Renalimpairment:Nodosageadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment(creatinine

clearancebetween30and50ml/min).

Elderly:Theclearanceofropiniroleisdecreasedinpatientsover65yearsofage.Theincreaseindosageshouldbe

gradualandtitratedagainstthesymptomaticresponse.

Childrenandadolescents:Ropiniroleisnotrecommendedforuseinchildrenandadolescentsbelow18yearsduetoa

lackofdataonsafetyandefficacy.

4.3Contraindications

Eironil2mgFilm-coatedTablets

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients

Severerenalimpairment(creatinineclearance<30ml/min)

Hepaticimpairment

4.4Specialwarningsandprecautionsforuse

Duetothepharmacologicalactionofropinirole,patientswithseverecardiovasculardisease(inparticularcoronary

insufficiency)shouldbetreatedwithcautionduetotheriskofhypotension;bloodpressuremonitoringis

recommended,particularlyatthebeginningoftreatment.

Co-administrationofropinirolewithanti-hypertensiveandanti-arrhythmicagentshasnotbeenstudied.Cautionshould

beexercisedwhenthesecompoundsaregivenconcomitantlywithropinirolebecauseoftheunknownpotentialforthe

occurrenceofhypotension,bradycardiasorotherarrhythmias.

Patientswithahistoryorpresenceofpsychiatricorpsychoticdisordersshouldonlybetreatedwithdopamineagonists

ifthepotentialbenefitsoutweightherisks(seealsosection4.5).

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

Week 2 3 4 5* 6* 7*

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Ropinirolehasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset(seesection4.8),particularlyin

patientswithParkinson'sDisease.Suddenonsetofsleepduringdailyactivities,insomecaseswithoutawarenessor

warningsigns,hasbeenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhile

drivingoroperatingmachinesduringtreatmentwithropinirole.Patientswhohaveexperiencedsomnolenceand/oran

episodeofsuddensleeponsetmustrefrainfromdrivingoroperatingmachines.Furthermore,areductionofdosageor

terminationoftherapymaybeconsidered.

Ropiniroleshouldnotbeusedtotreatneurolepticakathisia,tasikinesia(neuroleptic-inducedcompulsivetendencyto

walk),orsecondaryRestlessLegsSyndrome(e.g.causedbyrenalfailure,irondeficiencyanaemiaorpregnancy).

Duringtreatmentwithropinirole,paradoxicalworseningofRestlessLegsSyndromesymptomsoccurringwithearlier

onset(augmentation),andreoccurrenceofsymptomsintheearlymorninghours(earlymorningrebound),maybe

observed.Ifthisoccurs,treatmentshouldbereviewedanddosageadjustmentordiscontinuationoftreatmentmaybe

considered.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

RopiniroleisprincipallymetabolizedbythecytochromeP450isoenzymeCYP1A2.Apharmacokineticstudy(witha

ropiniroledoseof2mg,threetimesaday)revealedthatciprofloxacinincreasedtheC

andAUCofropiniroleby

60%and84%respectively,withapotentialriskofadverseevents.Hence,inpatientsalreadyreceivingropinirole,the

doseofropinirolemayneedtobeadjustedwhenmedicinalproductsknowntoinhibitCYP1A2,e.g.ciprofloxacin,

enoxacin,fluvoxamineorcimetidine,areintroducedorwithdrawn.

Apharmacokineticinteractionstudybetweenropinirole(atadoseof2mg,threetimesaday)andtheophylline,a

substrateofCYP1A2,revealednochangeinthepharmacokineticsofeitherropiniroleortheophylline.Therefore,itis

notexpectedthatropinirolewillcompetewiththemetabolismofothermedicinalproductswhicharemetabolisedby

CYP1A2.

Basedonin-vitrodata,ropinirolehaslittlepotentialtoinhibitcytochromeP450attherapeuticdoses.Hence,ropinirole

isunlikelytoaffectthepharmacokineticsofothermedicinalproducts,viaacytochromeP450mechanism.

SmokingisknowntoinduceCYP1A2metabolism,thereforeifpatientsstoporstartsmokingduringtreatmentwith

ropinirole,doseadjustmentmayberequired.

Increasedplasmaconcentrationsofropinirolehavebeenobservedinpatientstreatedwithhighdosesofoestrogens.In

patientsalreadyreceivinghormonereplacementtherapy(HRT),ropiniroletreatmentmaybeinitiatedinthenormal

manner.However,itmaybenecessarytoadjusttheropiniroledose,inaccordancewithclinicalresponse,ifhormone

replacementtherapyisstoppedorintroducedduringtreatmentwithropinirole.

Nopharmacokineticinteractionhasbeenseenbetweenropiniroleandlevodopaordomperidone(amedicinalproduct

usedtotreatnauseaandvomiting)whichwouldnecessitatedosageadjustmentofeithermedicinalproduct.

Domperidoneantagonisesthedopaminergicactionsofropiniroleperipherallyanddoesnotcrosstheblood-brain

barrier.Henceitsvalueasananti-emeticinpatientstreatedwithcentrallyactingdopamineagonists.

Neurolepticsandothercentrallyactivedopamineantagonists,suchassulpirideormetoclopramide,maydiminishthe

effectivenessofropiniroleand,therefore,concomitantuseofthesemedicinalproductswithropiniroleshouldbe

avoided.

4.6Pregnancyandlactation

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Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Asthepotentialriskforhumansisunknown,it

isrecommendedthatropiniroleisnotusedduringpregnancyunlessthepotentialbenefittothepatientoutweighsthe

potentialrisktothefoetus.

Ropiniroleshouldnotbeusedinnursingmothersasitmayinhibitlactation.

4.7Effectsonabilitytodriveandusemachines

Ropinirolehasmajorinfluenceontheabilitytodriveandusemachines.

Patientsshouldbewarnedaboutthepossibilityofdizziness(includingvertigo).Patientsbeingtreatedwithropinirole

andpresentingwithsomnolenceand/orsuddensleepepisodesmustbeinformedtorefrainfromdrivingorengagingin

activitieswhereimpairedalertnessmayputthemselvesorothersatriskofseriousinjuryordeath(e.g.operating

machines)untilsucheffectshaveresolved(seealsoSection4.4).

4.8Undesirableeffects

Undesirableeffectsarelistedbelowbysystemorganclassandfrequency.Frequenciesaredefinedas: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),notknown(cannotbeestimatedfromtheavailabledata).

Commonanduncommonundesirableeffectsweregenerallydeterminedfrompooledsafetydatafromclinicaltrial

populationsofropiniroleandarequotedasexcessincidenceoverplacebo.Rareandveryrareundesirableeffectswere

generallydeterminedfrompost-marketingdataandrefertoreportingrateratherthantruefrequency.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

AdverseDrugReactionsReportedfromPatientstakingropiniroleinParkinson’sDisease:

TheadversedrugreactionsreportedinpatientswithParkinson’sdiseaseonropinirolemonotherapyandadjunct

therapyatdosesupto24mg/dayatanexcessincidenceoverplaceboaredescribedbelow.

Themostcommonlyreportedundesirableeffectsarenausea,somnolence,dyskinesiaandsyncope.

Psychiatricdisorders

common confusion¹,hallucinations

uncommon Psychoticreactions(otherthanhallucinations),

includingdelusion,paranoia,delirium.

PatientstreatedwithdopamineagonistsfortreatmentofParkinson'sdisease,including

ropinirole,especiallyathighdoses,havebeenreportedasexhibitingsignsofpathological

gambling,increasedlibidoandhypersexuality,generallyreversibleuponreductionofthedose

ortreatmentdiscontinuation 3

Nervoussystemdisorders

Verycommon Syncope²,dyskinesia¹,somnolence²

common

dizziness(includingvertigo)¹ ,

uncommon extremedaytimesomnolence³suddenonsetofsleep³

Vasculardisorders

uncommon hypotension,posturalhypotension

Gastrointestinaldisorders

Verycommon nausea

common vomiting²,abdominalpain²,heartburn²

Generaldisordersandadministrativesiteconditions

common legoedema²

Hepatobiliarydisorders

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1Adjuncttherapystudies

2Monotherapystudies

3Post-marketingdata(seeSection4.4)

UseofropiniroleinRestlessLegsSyndrome

InRestlessLegsSyndromeclinicaltrialsthemostcommonadversedrugreactionwasnausea(approximately30%of

patients).Undesirableeffectswerenormallymildtomoderateandexperiencedatthestartoftherapyoronincreaseof

doseandfewpatientswithdrewfromtheclinicalstudiesduetoundesirableeffects.

Thetablebelowliststheadversedrugreactionsreportedforropiniroleinthe12-weekclinicaltrialsat1.0%abovethe

placeborateorthosereporteduncommonlybutknowntobeassociatedwithropinirole.

Adversedrugreactionsreportedin12-weekRestlessLegsSyndromeclinicaltrials(ropinirolen=309,placebon=307)

Hallucinationswerereporteduncommonlyintheopenlabellong-termstudies.

Inpost-marketingreports,extremedaytimesomnolenceandsuddenonsetofsleephavebeenreportedveryrarelyin

RestlessLegsSyndrome.

ParadoxicalworseningofRestlessLegsSyndromesymptomsoccurringwithearlieronset(augmentation),and

reoccurrenceofsymptomsintheearlymorninghours(earlymorningrebound),maybeobservedduringtreatmentwith

ropinirole.

Managementofundesirableeffects

Dosereductionshouldbeconsideredifpatientsexperiencesignificantundesirableeffects.Iftheundesirableeffect

abates,gradualup-titrationcanbere-instituted.Anti-nauseamedicinalproductsthatarenotcentrallyactivedopamine

antagonists,suchasdomperidone,maybeused,ifrequired.

4.9Overdose

Therehavebeennoincidencesofintentionaloverdosewithropiniroleinclinicaltrials.Itisanticipatedthatthe

symptomsofropiniroleoverdosewillberelatedtoitsdopaminergicactivity.Thesesymptomsmaybealleviatedby

appropriatetreatmentwithdopamineantagonistssuchasneurolepticsormetoclopramide.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Dopamineagonist,ATCcode:N04BC04.

Mechanismofaction

Psychiatricdisorders

Common Nervousness

Uncommon Confusion

Nervoussystemdisorders

Common Syncope,somnolence,dizziness(includingvertigo)

Vasculardisorders

Uncommon Posturalhypotension,hypotension

Gastrointestinaldisorders

Verycommon Vomiting,nausea

Common Abdominalpain

Generaldisordersandadministrationsiteconditions

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Parkinson'sdiseaseischaracterisedbyamarkeddopaminedeficiencyinthenigralstriatalsystem.Ropinirole

alleviatesthisdeficiencybystimulatingstriataldopaminereceptors.

Ropiniroleactsinthehypothalamusandpituitarytoinhibitthesecretionofprolactin.

ClinicalefficacyinRestlessLegsSyndrome

RopiniroleshouldonlybeprescribedtopatientswithmoderatetosevereidiopathicRestlessLegsSyndrome.Moderate

tosevereidiopathicRestlessLegsSyndromeistypicallyrepresentedbypatientswhosufferwithinsomniaorsevere

discomfortinthelimbs.

Inthefour12-weekefficacystudies,patientswithRestlessLegsSyndromewererandomisedtoropiniroleorplacebo,

andtheeffectsontheIRLSscalescoresatweek12werecomparedtobaseline.Themeandoseofropiniroleforthe

moderatetoseverepatientswas2.0mg/day.InacombinedanalysisofmoderatetosevereRestlessLegsSyndrome

patientsfromthefour12-weekstudies,theadjustedtreatmentdifferenceforthechangefrombaselineinIRLSscale

totalscoreatweek12LastObservationCarriedForward(LOCF)IntentionToTreatpopulationwas-4.0points(95%

CI-5.6,-2.4,p<0.0001;baselineandweek12LOCFmeanIRLSpoints:ropinirole28.4and13.5;placebo28.2and

17.4).

A12-weekplacebo-controlledpolysomnographystudyinRestlessLegsSyndromepatientsexaminedtheeffectof

treatmentwithropiniroleonperiodiclegmovementsofsleep.Astatisticallysignificantdifferenceintheperiodicleg

movementsofsleepwasseenbetweenropiniroleandplacebofrombaselinetoweek12.

AlthoughsufficientdataarenotavailabletoadequatelydemonstratethelongtermefficacyofropiniroleinRestless

LegsSyndrome(seesection4.2),ina36-weekstudy,patientswhocontinuedonropiniroledemonstratedasignificantly

lowerrelapseratecomparedwithpatientsrandomisedtoplacebo(33%versus58%,p=0.0156).

AcombinedanalysisofdatafrommoderatetosevereRestlessLegsSyndromepatients,inthefour12-week

placebo-controlledstudies,indicatedthatropinirole-treatedpatientsreportedsignificantimprovementsoverplaceboon

theparametersoftheMedicalOutcomeStudySleepScale(scoreson0-100rangeexceptsleepquantity).Theadjusted

treatmentdifferencesbetweenropiniroleandplacebowere:sleepdisturbance(-15.2,95%CI-19.37,-10.94;

p<0.0001),sleepquantity(0.7hours,95%CI0.49,0.94);p<0.0001),sleepadequacy(18.6,95%CI13.77,23.45;

p<0.0001)anddaytimesomnolence(-7.5,95%CI-10.86,-4.23;p<0.0001).

Areboundphenomenonfollowingdiscontinuationofropiniroletreatment(endoftreatmentrebound)cannotbe

excluded.Inclinicaltrials,althoughtheaverageIRLStotalscores7-10daysafterwithdrawaloftherapywerehigher

inropinirole-treatedpatientsthaninplacebo-treatedpatients,theseverityofsymptomsfollowingwithdrawaloftherapy

generallydidnotexceedthebaselineassessmentinropinirole-treatedpatients.

InclinicalstudiesmostpatientswereofCaucasianorigin.

5.2Pharmacokineticproperties

Absorption

Thebioavailabilityofropiniroleisabout50%(36%to57%),withC

reachedonaverage1.5hoursafterthedose.In

thepresenceoffood,C

isdelayedbyabout2.6hoursandthepeakplasmalevelisreducedby25%,withnoeffect

onthebioavailablequantity.Thebioavailabilityofropinirolevariesgreatlybetweenindividuals.

Distribution

Thebindingofropiniroletoplasmaproteinsisnothigh(<40%),withnoeffectonthedistributionwhichisvery

extensive(volumeofdistributionintheorderof7l/kg).

Metabolism

RopiniroleismainlymetabolisedbytheisoformCYP1A2ofcytochromeP450.Noneofthemanymetabolitesformed

areinvolvedintheresultingactivityoftheproductandthemainmetaboliteis100timeslesspotentthanropinirolein

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Elimination

Unchangedropiniroleandthemetabolitesaremainlyexcretedthroughthekidneys.Theeliminationhalf-lifeof

ropiniroleis6hoursonaverage.

Linearity

Thepharmacokineticsofropinirolearelinearoverall(C

andAUC)inthetherapeuticrangebetween0.25mgand

4mg,afterasingledoseandafterrepeateddosing.

Population-relatedcharacteristics

Inpatientsover65yearsofage,areductioninthesystemicclearanceofropinirolebyabout30%ispossible.

Inpatientswithmildtomoderaterenalimpairment(creatinineclearancebetween30and50ml/min),nochangeinthe

pharmacokineticsofropiniroleisobserved.Nodataareavailableinpatientswithsevererenalimpairment.

5.3Preclinicalsafetydata

Toxicology:Thetoxicologyprofileisprincipallydeterminedbythepharmacologicalactivityofthedrug(behavioural

changes,hypoprolactinaemia,decreaseinbloodpressureandheartrate,ptosisandsalivation).Inthealbinoratonly,

retinaldegenerationwasobservedinalongtermstudyatahighdose(50mg/kg),probablyassociatedwithan

increasedexposuretolight.

Genotoxicity:Genotoxicitywasnotobservedintheusualbatteryofinvitroandinvivotests.

Carcinogenicity:Fromtwo-yearstudiesconductedinthemouseandratatdosagesupto50mg/kgtherewasno

evidenceofanycarcinogeniceffectinthemouse.Intherat,theonlydrug-relatedlesionswereLeydigcellhyperplasia

andtesticularadenomaresultingfromthehypoprolactinaemiceffectofropinirole.Theselesionsareconsideredtobea

speciesspecificphenomenonanddonotconstituteahazardwithregardtotheclinicaluseofropinirole.

ReproductiveToxicity:Administrationofropiniroletopregnantratsatmaternallytoxicdosesresultedindecreased

foetalbodyweightat60mg/kg/day(approximatelyequivalenttotheAUCatthemaximumdoseinhumans),increased

foetaldeathat90mg/kg/day(approximately2timestheAUCatthemaximumdoseinhumans)anddigit

malformationsat150mg/kg/day(approximately3timestheAUCatthemaximumdoseinhumans).Therewereno

teratogeniceffectsintheratat120mg/kg/day(approximately2.5timestheAUCatthemaximumdoseinhumans)and

noindicationofaneffectondevelopmentintherabbit.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Cellulose,microcrystalline

Maizestarch

Silicacolloidalanhydrous

Magnesiumstearate

Filmcoating:

OpadryII31F58914Whiteconsistingof:

Hypromellose15cp(E464)

Lactosemonohydrate

Titaniumdioxide(E171)

Macrogol4000

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

18months

6.4Specialprecautionsforstorage

Donotstoreabove25 °

C.Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Al//PVC/Al/oPAfoilblisters

2mg:Packsof21,28and84film-coatedtablets

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposal

NoSpecialRequirements.

7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLimited

VisionHouse

BedfordRoad

Petersfield

Hampshire

GU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA585/32/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12 th

December2008

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