DERINIK

Main information

  • Trade name:
  • DERINIK Tablets 0.088 Milligram
  • Dosage:
  • 0.088 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DERINIK Tablets 0.088 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/106/001
  • Authorization date:
  • 26-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Derinik0.088mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Derinik0.088mgtabletscontain0.088mgofpramipexolebase(as0.125mgofpramipexoledihydrochloride

monohydrate).

Pleasenote:

Pramipexoledosesaspublishedintheliteraturerefertothesaltform.

Therefore,doseswillbeexpressedintermsofbothpramipexolebaseandpramipexolesalt(inbrackets).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

White,roundtablets,markedononesidewitha“0”(zero),withnodefectsanddimensions6.0±0.1mmindiameter

and3.0mm±0.2mminthickness.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DerinikisindicatedinadultsfortreatmentofthesignsandsymptomsofidiopathicParkinson'sdisease,alone(without

levodopa)orincombinationwithlevodopa,i.e.overthecourseofthedisease,throughtolatestageswhentheeffectof

levodopawearsofforbecomesinconsistentandfluctuationsofthetherapeuticeffectoccur(endofdoseor“onoff”

fluctuations).

4.2Posologyandmethodofadministration

Posology

Parkinson’sdisease

Thedailydoseisadministeredinequallydivideddoses3timesaday.

Initialtreatment

Dosesshouldbeincreasedgraduallyfromastartingdoseof0.264mgofbase(0.375mgofsalt)perdayandthen

increasedevery5-7days.Providingpatientsdonotexperienceintolerableundesirableeffects,thedoseshouldbe

titratedtoachieveamaximaltherapeuticeffect.

Ifafurtherdoseincreaseisnecessarythedailydoseshouldbeincreasedby0.54mgofbase(0.75mgofsalt)atweekly

intervalsuptoamaximumdoseof3.3mgofbase(4.5mgofsalt)perday.

ASCENDINGDOSESCHEDULEOFPRIXOL

Week Dose

(mgofbase) TotalDailyDose

(mgofbase) Dose

(mgofsalt) TotalDailyDose

(mgofsalt)

3x0.088 0.264 3x0.125 0.375

3x0.18 0.54 3x0.25 0.75

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(seesection4.8).

Maintenancetreatment

Theindividualdoseofpramipexoleshouldbeintherangeof0.264mgofbase(0.375mgofsalt)toamaximumof3.3

mgofbase(4.5mgofsalt)perday.Duringdoseescalationinpivotalstudies,efficacywasobservedstartingatadaily

doseof1.1mgofbase(1.5mgofsalt).Furtherdoseadjustmentsshouldbedonebasedontheclinicalresponseandthe

occurrenceofadversereactions.Inclinicaltrialsapproximately5%ofpatientsweretreatedatdosesbelow1.1mgof

base(1.5mgofsalt).InadvancedParkinson’sdisease,pramipexoledoseshigherthan1.1mgofbase(1.5mgofsalt)

perdaycanbeusefulinpatientswhereareductionofthelevodopatherapyisintended.Itisrecommendedthatthedose

oflevodopaisreducedduringboththedoseescalationandthemaintenancetreatmentwithpramipexole,dependingon

reactionsinindividualpatients(seesection4.5).

Treatmentdiscontinuation

Abruptdiscontinuationofdopaminergictherapycanleadtothedevelopmentofaneurolepticmalignantsyndrome.

Therefore,pramipexoleshouldbetaperedoffatarateof0.54mgofbase(0.75mgofsalt)perdayuntilthedailydose

hasbeenreducedto0.54mgofbase(0.75mgofsalt).Thereafterthedoseshouldbereducedby0.264mgofbase

(0.375mgofsalt)perday(seesection4.4).

Dosinginpatientswithrenalimpairment

Theeliminationofpramipexoleisdependentonrenalfunction.Thefollowingdosescheduleissuggestedforinitiation

oftherapy:

Patientswithacreatinineclearanceabove50ml/minrequirenoreductionindailydoseordosingfrequency.

Inpatientswithacreatinineclearancebetween20and50ml/min,theinitialdailydoseofpramipexoleshouldbe

administeredintwodivideddoses,startingat0.088mgofbase(0.125mgofsalt)twiceaday(0.176mgofbase/0.25

mgofsaltdaily).Amaximumdailydoseof1.57mgpramipexolebase(2.25mgofsalt)shouldnotbeexceeded.

Inpatientswithacreatinineclearancelessthan20ml/min,thedailydoseofpramipexoleshouldbeadministeredina

singledose,startingat0.088mgofbase(0.125mgofsalt)daily.Amaximumdailydoseof1.1mgpramipexolebase

(1.5mgofsalt)shouldnotbeexceeded.

Ifrenalfunctiondeclinesduringmaintenancetherapythepramipexoledailydoseshouldbereducedbythesame

percentageasthedeclineincreatinineclearance,i.e.ifcreatinineclearancedeclinesby30%,thenthepramipexole

dailydoseshouldbereducedby30%.Thedailydosecanbeadministeredintwodivideddosesifcreatinineclearance

isbetween20and50ml/minandasasingledailydoseifcreatinineclearanceislessthan20ml/min.

Dosinginpatientswithhepaticimpairment

Doseadjustmentinpatientswithhepaticfailureisprobablynotnecessary,asapprox.90%ofabsorbedactivesubstance

isexcretedthroughthekidneys.However,thepotentialinfluenceofhepaticinsufficiencyonpramipexole

pharmacokineticshasnotbeeninvestigated.

Paediatricpopulation

ThesafetyandefficacyofPRAMIPEXOLEinchildrenbelow18yearshasnotbeenestablished.Thereisnorelevant

useofpramipexoleinthepaediatricpopulationinParkinson’sDisease.

RestlessLegsSyndrome

Therecommendedstartingdoseofpramipexoleis0.088mgofbase(0.125mgofsalt)takenoncedaily2-3hours

beforebedtime.Forpatientsrequiringadditionalsymptomaticrelief,thedosemaybeincreasedevery4-7daystoa

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Patient’sresponseshouldbeevaluatedafter3monthstreatmentandtheneedfortreatmentcontinuationshouldbe

reconsidered.Iftreatmentisinterruptedformorethanafewdaysitshouldbere-initiatedbydosetitrationcarriedout

asabove.

Treatmentdiscontinuation

SincethedailydoseforthetreatmentofRestlessLegsSyndromewillnotexceed0.54mgofbase(0.75mgofsalt)

pramipexolecanbediscontinuedwithouttaperingoff.Ina26weekplacebocontrolledtrial,reboundofRLSsymptoms

(worseningofsymptomseverityascomparedtobaseline)wasobservedin10%ofpatients(14outof135)afterabrupt

discontinuationoftreatment.Thiseffectwasfoundtobesimilaracrossalldoses.

Dosinginpatientswithrenalimpairment

Theeliminationofpramipexoleisdependentonrenalfunction.Patientswithacreatinineclearanceabove20ml/min

requirenoreductionindailydose.

Theuseofpramipexolehasnotbeenstudiedinhaemodialysispatients,orinpatientswithsevererenalimpairment.

Dosinginpatientswithhepaticimpairment

Doseadjustmentinpatientswithhepaticfailureisnotrequired,asapprox.90%ofabsorbedactivesubstanceis

excretedthroughthekidneys.

Paediatricpopulation

Pramipexoleisnotrecommendedforuseinchildrenandadolescentsbelow18yearsduetoalackofdataonsafetyand

efficacy.

TouretteDisorder

Paediatricpopulation

Pramipexoleisnotrecommendedforuseinchildrenandadolescentsbelow18yearssincetheefficacyandsafetyhas

notbeenestablishedinthispopulation.PramipexoleshouldnotbeusedinchildrenoradolescentswithTourette

Disorderbecauseofanegativebenefit-riskbalanceforthisdisorder(see

section5.1).

Methodofadministration

Thetabletsshouldbetakenorally,swallowedwithwater,andcanbetakeneitherwithorwithoutfood.

4.3Contraindications

Hypersensitivitytoactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

WhenprescribingpramipexoleinapatientwithParkinson’sdiseasewithrenalimpairmentareduceddoseissuggested

inlinewithsection4.2.

Hallucinations

Hallucinationsareknownasasideeffectoftreatmentwithdopamineagonistsandlevodopa.Patientsshouldbe

informedthat(mostlyvisual)hallucinationscanoccur.

Dyskinesia

InadvancedParkinson’sdisease,incombinationtreatmentwithlevodopa,dyskinesiacanoccurduringtheinitial

titrationofPRAMIPEXOLE.Iftheyoccur,thedoseoflevodopashouldbedecreased.

Suddenonsetofsleepandsomnolence

Pramipexolehasbeenassociatedwithsomnolenceandepisodesofsuddensleeponset,particularlyinpatientswith

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hasbeenreporteduncommonly.Patientsmustbeinformedofthisandadvisedtoexercisecautionwhiledrivingor

operatingmachinesduringtreatmentwithpramipexole.

Patientswhohaveexperiencedsomnolenceand/oranepisodeofsuddensleeponsetmustrefrainfromdrivingor

operatingmachines.Furthermoreareductionofthedoseorterminationoftherapymaybeconsidered.Becauseof

possibleadditiveeffects,cautionshouldbeadvisedwhenpatientsaretaking

othersedatingmedicinalproductsoralcoholincombinationwithpramipexole(seesections4.5,4.7andsection4.8).

Impulsecontroldisordersandcompulsivebehaviours

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson’sdisease,includingpramipexole.Furthermore,patientsandcaregiversshouldbeawareofthe

factthatotherbehaviouralsymptomsofimpulsecontroldisordersandcompulsionssuchasbingeeatingand

compulsiveshoppingcanoccur.Dosereduction/tapereddiscontinuationshouldbeconsidered.

Patientswithpsychoticdisorders

Patientswithpsychoticdisordersshouldonlybetreatedwithdopamineagonistsifthepotentialbenefitsoutweighthe

risks.Co-administrationofantipsychoticmedicinalproductswithpramipexoleshouldbeavoided(seesection4.5).

Ophthalmologicmonitoring

Ophthalmologicmonitoringisrecommendedatregularintervalsorifvisionabnormalitiesoccur.

Severecardiovasculardisease

Incaseofseverecardiovasculardisease,careshouldbetaken.Itisrecommendedtomonitorbloodpressure,especially

atthebeginningoftreatment,duetothegeneralriskofposturalhypotensionassociatedwithdopaminergictherapy.

Neurolepticmalignantsyndrome

Symptomssuggestiveofneurolepticmalignantsyndromehavebeenreportedwithabruptwithdrawalofdopaminergic

therapy(seesection4.2).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Plasmaproteinbinding

Pramipexoleisboundtoplasmaproteinstoaverylow(<20%)extent,andlittlebiotransformationisseeninman.

Therefore,interactionswithothermedicinalproductsaffectingplasmaproteinbindingoreliminationby

biotransformationareunlikely.Asanticholinergicsaremainlyeliminatedbybiotransformation,thepotentialforan

interactionislimited,althoughaninteractionwithanticholinergicshasnotbeeninvestigated.Thereisno

pharmacokineticinteractionwithselegilineandlevodopa.

Inhibitors/competitorsofactiverenaleliminationpathway

Cimetidinereducedtherenalclearanceofpramipexolebyapproximately34%,presumablybyinhibitionofthecationic

secretorytransportsystemoftherenaltubules.Therefore,medicinalproductsthatareinhibitorsofthisactiverenal

eliminationpathwayorareeliminatedbythispathway,suchascimetidine,amantadine,andmexiletine,mayinteract

withpramipexoleresultinginreducedclearanceofeitherorbothmedicinalproducts.Reductionofthepramipexole

doseshouldbeconsideredwhenthesemedicinalproductsareadministeredconcomitantlywithpramipexole.

Combinationwithlevodopa

Whenpramipexoleisgivenincombinationwithlevodopa,itisrecommendedthatthedoseoflevodopaisreducedand

thedoseofotheranti-parkinsonianmedicinalproductsiskeptconstantwhileincreasingthedoseofpramipexole.

Becauseofpossibleadditiveeffects,cautionshouldbeadvisedwhenpatientsaretakingothersedatingmedicinal

productsoralcoholincombinationwithpramipexole(seesection4.4,4.7and4.8).

Antipsychoticmedicinalproducts

Co-administrationofantipsychoticmedicinalproductswithpramipexoleshouldbeavoided(seesection4.4),e.g.if

antagonisticeffectscanbeexpected.

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Pregnancy

Theeffectonpregnancyandlactationhasnotbeeninvestigatedinhumans.Pramipexolewasnotteratogenicinratsand

rabbits,butwasembryotoxicintheratatmaternotoxicdoses(seesection5.3).pramipexoleshouldnotbeusedduring

pregnancyunlessclearlynecessary,i.e.ifthepotentialbenefit

justifiesthepotentialrisktothefoetus.

Brest-feeding

Aspramipexoletreatmentinhibitssecretionofprolactininhumans,inhibitionoflactationisexpected.Theexcretionof

pramipexoleintobreastmilkhasnotbeenstudiedinwomen.Inrats,theconcentrationofactivesubstance-related

radioactivitywashigherinbreastmilkthaninplasma.Intheabsenceofhumandata,pramipexoleshouldnotbeused

duringbreast-feeding.However,ifitsuseisunavoidable,breast-feedingshouldbediscontinued.

Fertility

Nohumanornon-clinicalfertilitydataareavailable.

4.7Effectsonabilitytodriveandusemachines

Pramipexolecanhaveamajorinfluenceontheabilitytodriveandusemachines.

Hallucinationsorsomnolencecanoccur.

Patientsbeingtreatedwithpramipexoleandpresentingwithsomnolenceand/orsuddensleepepisodesmustbe

informedtorefrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersatrisk

ofseriousinjuryordeath(e.g.operatingmachines)untilsuchrecurrentepisodesandsomnolencehaveresolved(see

alsosections4.4,4.5and4.8).

4.8Undesirableeffects

Expectedadversereactions

Thefollowingadversereactionsareexpectedundertheuseofpramipexole:abnormaldreams,amnesia,behavioural

symptomsofimpulsecontroldisordersandcompulsionssuchasbingeeating,compulsiveshopping,hypersexuality

andpathologicalgambling;confusion,constipation,delusion,dizziness,dyskinesia,dyspnoea,fatigue,hallucinations,

headache,hyperkinesia,hyperphagia,hypotension,insomnia,libidodisorders,nausea,paranoia,peripheraloedema,

pneumonia,pruritus,rashandotherhypersensitivity;restlessness,somnolence,suddenonsetofsleep,syncope,visual

disturbanceincludingvisionblurredandvisualacuityreduced,vomiting,weightdecrease,weightincrease.

Basedontheanalysisofpooledplacebo-controlledtrials,comprisingatotalof1,923patientsonpramipexoleand

1,354patientsonplacebo,adversedrugreactionswerefrequentlyreportedforbothgroups.63%ofpatientson

pramipexoleand52%ofpatientsonplaceboreportedatleastoneadversedrugreaction.

Tables1and2displaythefrequencyofadversedrugreactionsfromplacebo-controlledclinicaltrialsinParkinson’s

diseaseandRestlessLegsSyndrome.Theadversedrugreactionsreportedinthesetablesarethoseeventsthatoccurred

in0.1%ormoreofpatientstreatedwithpramipexoleandwerereportedsignificantlymoreofteninpatientstaking

pramipexolethanplacebo,orwheretheeventwasconsideredclinicallyrelevant.Themajorityofadversedrug

reactionsweremildtomoderate,theyusuallystartearlyintherapyandmosttendedtodisappearevenastherapywas

continued.

Withinthesystemorganclasses,adversereactionsarelistedunderheadingsoffrequency(numberofpatientsexpected

toexperiencethereaction),usingthefollowingcategories: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(cannotbe

estimatedfromtheavailabledata).

Parkinson’sdisease,mostcommonadversereactions

Themostcommonly( ≥5%)reportedadversedrugreactionsinpatientswithParkinson’sdiseasemorefrequentwith

pramipexoletreatmentthanwithplacebowerenausea,dyskinesia,hypotension,dizziness,somnolence,insomnia,

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somnolenceisincreasedatdoseshigherthan1.5mgpramipexolesaltperday(seesection4.2).Amorefrequent

adversedrugreactionincombinationwithlevodopawasdyskinesia.Hypotensionmayoccuratthebeginningof

treatment,especiallyifpramipexoleistitratedtoofast.

Table1:Parkinson’sdisease

RestlessLegsSyndrome,mostcommonadversereactions

Themostcommonly( ≥5%)reportedadversedrugreactionsinpatientswithRestlessLegsSyndrometreatedwith

pramipexolewerenausea,headache,dizzinessandfatigue.Nauseaandfatigueweremoreoftenreportedinfemale

patientstreatedwithpramipexole(20.8%and10.5%,respectively)comparedtomales(6.7%and7.3%,respectively).

SystemOrganClass AdverseDrugReaction

Infectionsandinfestations

Uncommon pneumonia

Psychiatricdisorders

Common abnormaldreams,behaviouralsymptomsof

impulsecontroldisordersandcompulsions;

confusion,hallucinations,insomnia,restlessness

Uncommon compulsiveshopping,delusion,hypersexuality,

libidodisorder,paranoia,pathologicalgambling

Notknown bingeeating,hyperphagia

Nervoussystemdisorders

Verycommon dizziness,dyskinesia,somnolence

Common amnesia,headache

Uncommon hyperkinesia,suddenonsetofsleep,syncope

Eyedisorders

Common visualdisturbanceincludingvisionblurredand

visualacuityreduced

Vasculardisorders

Verycommon hypotension

Respiratory,thoracic,andmediastinaldisorders

Uncommon dyspnoea

Gastrointestinaldisorders

Verycommon nausea

Common Constipation,vomiting

Skinandsubcutaneoustissuedisorders

Uncommon hypersensitivity,pruritus,rash

Generaldisordersandadministrationsiteconditions

Common fatigue,peripheraloedema

Investigations

Common weigthdecrease

Uncommon weightincrease

SystemOrganClass AdverseDrugReaction

Infectionsandinfestations

Notknown pneumonia

Psychiatricdisorders

Common abnormaldreams,insomnia

Uncommon confusion,hallucinations,libidodisorder,

restlessness

Notknown behaviouralsymptomsofimpulsecontroldisorders

andcompulsionssuchasbingeeating,compulsive

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Somnolence

Pramipexoleiscommonlyassociatedwithsomnolenceandhasbeenassociateduncommonlywithexcessivedaytime

somnolenceandsuddensleeponsetepisodes(seealsosection4.4).

Libidodisorders

Pramipexolemayuncommonlybeassociatedwithlibidodisorders(increasedordecreased).

Impulsecontroldisordersandcompulsivebehaviours

PatientstreatedwithdopamineagonistsforParkinson’sdisease,includingpramipexole,especiallyathighdoses,have

beenreportedasexhibitingsignsofpathologicalgambling,increasedlibidoandhypersexuality,generallyreversible

uponreductionofthedoseortreatmentdiscontinuation(seealso

section4.4).

Inacross-sectional,retrospectivescreeningandcase-controlstudyincluding3,090Parkinson’sdiseasepatients,13.6%

ofallpatientsreceivingdopaminergicornon-dopaminergictreatmenthadsymptomsofanimpulsecontroldisorder

duringthepastsixmonths.Manifestationsobservedinclude

pathologicalgambling,compulsiveshopping,bingeeating,andcompulsivesexualbehaviour(hypersexuality).Possible

independentriskfactorsforimpulsecontroldisordersincludeddopaminergictreatmentsandhigherdosesof

dopaminergictreatment,youngerage( ≤65years),notbeingmarriedandself-reportedfamilyhistoryofgambling

behaviours.

4.9Overdose

Thereisnoclinicalexperiencewithmassiveoverdose.Theexpectedadversereactionswouldbethoserelatedtothe

pharmacodynamicprofileofadopamineagonist,includingnausea,vomiting,hyperkinesia,hallucinations,agitation

andhypotension.Thereisnoestablishedantidoteforoverdoseofadopamineagonist.Ifsignsofcentralnervous

systemstimulationarepresent,aneurolepticagentmaybeindicated.Managementoftheoverdosemayrequiregeneral

supportivemeasures,alongwithgastriclavage,intravenousfluids,administrationofactivatedcharcoaland

electrocardiogram

gambling;delusion,hyperphagia,paranoia,

Nervoussystemdisorders

Common dizziness,headache,somnolence

Uncommon suddenonsetofsleep,syncope

Notknown amnesia,dyskinesia,hyperkinesia

Eyedisorders

Uncommon visualdisturbanceincludingvisionblurredand

visualacuityreduced

Vasculardisorders

Uncommon hypotension

Respiratory,thoracic,andmediastinaldisorders

Uncommon dyspnoea

Gastrointestinaldisorders

Verycommon nausea

Common constipation,vomitting

Skinandsubcutaneoustissuedisorders

Uncommon hypersensitivity,pruritus,rash

Generaldisordersandadministrationsiteconditions

Common fatigue

Uncommon peripheraloedema

Investigations

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-Parkinsondrugs,dopamineagonists,ATCcode:N04BC05.

PramipexoleisadopamineagonistthatbindswithhighselectivityandspecificitytotheD2subfamilyofdopamine

receptorsofwhichithasapreferentialaffinitytoD3receptors,andhasfullintrinsicactivity.

Pramipexolealleviatesparkinsonianmotordeficitsbystimulationofdopaminereceptorsinthestriatum.Animal

studieshaveshownthatpramipexoleinhibitsdopaminesynthesis,release,andturnover.

ThemechanismofactionofpramipexoleastreatmentforRestlessLegsSyndromeisunknown.

Neuropharmacologicalevidencesuggestsprimarydopaminergicsysteminvolvement.

Inhumanvolunteers,adose-dependentdecreaseinprolactinwasobserved.

ClinicaltrialsinParkinson’sdisease

InpatientspramipexolealleviatessignsandsymptomsofidiopathicParkinson’sdisease.Placebocontrolledclinical

trialsincludedapproximately1,800patientsofHoehnandYahrstagesI–Vtreatedwithpramipexole.Outofthese,

approximately1,000wereinmoreadvancedstages,receivedconcomitantlevodopatherapy,andsufferedfrommotor

complications.InearlyandadvancedParkinson’sdisease,efficacyofpramipexoleincontrolledclinicaltrialswas

maintainedforapproximatelysixmonths.Inopencontinuationtrialslastingformorethanthreeyearstherewereno

signsofdecreasingefficacy.

Inacontrolleddoubleblindclinicaltrialof2yearduration,initialtreatmentwithpramipexolesignificantlydelayedthe

onsetofmotorcomplications,andreducedtheiroccurrencecomparedtoinitialtreatmentwithlevodopa.Thisdelayin

motorcomplicationswithpramipexoleshouldbebalancedagainstagreaterimprovementinmotorfunctionwith

levodopa(asmeasuredbythemeanchangeinUPDRS-score).Theoverallincidenceofhallucinationsandsomnolence

wasgenerallyhigherintheescalationphasewiththepramipexolegroup.However,therewasnosignificantdifference

duringthemaintenancephase.Thesepointsshouldbeconsideredwheninitiatingpramipexoletreatmentinpatients

withParkinson’sdisease.

ClinicaltrialsinRestlessLegsSyndrome

Theefficacyofpramipexolewasevaluatedinfourplacebo-controlledclinicaltrialsinapproximately1,000patients

withmoderatetoverysevereidiopathicRestlessLegsSyndrome.ThemeanchangefrombaselineintheRestlessLegs

SyndromeRatingScale(IRLS)andtheClinicalGlobalImpression-Improvement(CGI-I)weretheprimaryefficacy

outcomemeasures.Forbothprimaryendpointsstatisticallysignificantdifferenceshavebeenobservedforthe

pramipexoledosegroups0.25mg,0.5mgand0.75mgpramipexolesaltincomparisontoplacebo.After12weeksof

treatmentthebaselineIRLSscoreimprovedfrom23.5to14.1pointsforplaceboandfrom23.4to9.4pointsfor

pramipexole(dosescombined).Theadjustedmeandifferencewas-4.3points(CI95%-6.4;-2.1points,p-value

<0.0001).CGI-Iresponderrates(improved,verymuchimproved)were51.2%and72.0%forplaceboandpramipexole,

respectively(difference20%CI95%:8.1%;31.8%,p<0.0005).Efficacywasobservedwith0.088mgofbase(0.125

mgofsalt)perdayafterthefirstweekoftreatment.

Inaplacebo-controlledpolysomnographystudyover3weekspramipexolesignificantlyreducedthenumberofperiodic

limbmovementsduringtimeinbed.

Longertermefficacywasevaluatedinaplacebo-controlledclinicaltrial.After26weeksoftreatment,

therewasanadjustedmeanreductioninIRLStotalscoreof13.7and11.1pointsinthepramipexole

andplacebogroup,respectively,withastatisticallysignificant(p=0.008)meantreatmentdifference

of-2.6.CGI-Iresponderrates(muchimproved,verymuchimproved)were50.3%(80/159)and68.5%

(111/162)forplaceboandpramipexole,respectively(p=0.001),correspondingtoanumberneededto

treat(NNT)of6patients(95%CI:3.5,13.4).

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pramipexoleinoneormoresubsetsofthepaediatricpopulationinRestlessLegsSyndrome(seesection

4.2forinformationonpaediatricuse).

ClinicaltrialinTouretteDisorder

Theefficacyofpramipexole(0.0625-0.5mg/day)withpaediatricpatientsaged6-17yearswith

TouretteDisorderwasevaluatedina6-week,double-blind,randomised,placebo-controlledflexible

dosestudy.Atotalof63patientswererandomised(43onpramipexole,20onplacebo).Theprimary

endpointwaschangefrombaselineontheTotalTicScore(TTS)oftheYaleGlobalTicSeverity

Scale(YGTSS).Nodifferencewasobservedforpramipexoleascomparedtoplaceboforeitherthe

primaryendpointorforanyofthesecondaryefficacyendpointsincludingYGTSStotalscore,Patient

GlobalImpressionofImprovement(PGI-I),ClinicalGlobalImpressionofImprovement(CGI-I),or

ClinicalGlobalImpressionsofSeverityofIllness(CGI-S).Adverseeventsoccurringinatleast5%of

patientsinthepramipexolegroupandmorecommoninthepramipexole-treatedpatientsthanin

patientsonplacebowere:headache(27.9%,placebo25.0%),somnolence(7.0%,placebo5.0%),

nausea(18.6%,placebo10.0%),vomiting(11.6%,placebo0.0%),upperabdominalpain(7.0%,

placebo5.0%),orthostatichypotension(9.3%,placebo5.0%),myalgia(9.3%,placebo5.0%),sleep

disorder(7.0%,placebo0.0%),dyspnoea(7.0%,placebo0.0%)andupperrespiratorytractinfection

(7.0%,placebo5.0%).Othersignificantadverseeventsleadingtodiscontinuationofstudymedication

forpatientsreceivingpramipexolewereconfusionalstate,speechdisorderandaggravatedcondition

(seesection4.2).

5.2Pharmacokineticproperties

Pramipexoleisrapidlyandcompletelyabsorbedfollowingoraladministration.Theabsolutebioavailabilityisgreater

than90%andthemaximumplasmaconcentrationsoccurbetween1and3hours.Concomitantadministrationwithfood

didnotreducetheextentofpramipexoleabsorption,buttherateofabsorptionwasreduced.Pramipexoleshowslinear

kineticsandasmallinter-patientvariationofplasmalevels.Inhumans,theproteinbindingofpramipexoleisverylow

(<20%)andthevolumeofdistributionislarge(400l).Highbraintissueconcentrationswereobservedintherat

(approx.8-foldcomparedtoplasma).

Pramipexoleismetabolisedinmanonlytoasmallextent.

Renalexcretionofunchangedpramipexoleisthemajorrouteofelimination.Approximately90%of14C-labelleddose

isexcretedthroughthekidneyswhilelessthan2%isfoundinthefaeces.Thetotalclearanceofpramipexoleis

approximately500ml/minandtherenalclearanceisapproximately400ml/min.Theeliminationhalf-life(t½)varies

from8hoursintheyoungto12hoursintheelderly

5.3Preclinicalsafetydata

Repeateddosetoxicitystudiesshowedthatpramipexoleexertedfunctionaleffects,mainlyinvolvingtheCNSand

femalereproductivesystem,andprobablyresultingfromanexaggeratedpharmacodynamiceffectofpramipexole.

Decreasesindiastolicandsystolicpressureandheartratewerenotedintheminipig,andatendencytoahypotensive

effectwasdiscernedinthemonkey.

Thepotentialeffectsofpramipexoleonreproductivefunctionhavebeeninvestigatedinratsandrabbits.Pramipexole

wasnotteratogenicinratsandrabbitsbutwasembryotoxicintheratatmaternallytoxicdoses.Duetotheselectionof

animalspeciesandthelimitedparametersinvestigated,theadverseeffectsofpramipexoleonpregnancyandmale

fertilityhavenotbeenfullyelucidated.

Pramipexolewasnotgenotoxic.Inacarcinogenicitystudy,maleratsdevelopedLeydigcellhyperplasiaandadenomas,

explainedbytheprolactin-inhibitingeffectofpramipexole.Thisfindingisnotclinicallyrelevanttoman.Thesame

studyalsoshowedthat,atdosesof2mg/kg(ofsalt)andhigher,pramipexolewasassociatedwithretinaldegeneration

inalbinorats.Thelatterfindingwasnotobservedinpigmentedrats,norina2-yearalbinomousecarcinogenicitystudy

orinanyotherspeciesinvestigated.

Irish Medicines Board

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Date Printed 28/04/2011 CRN 2084410 page number: 9

6.1Listofexcipients

Starch,pregelatinised(Starchmaize1500)

Mannitol

Cellulose,microcrystalline

Povidone(27.0-32.4)

Talc

Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

Blister(PA/ALU/PVC-Aluminium):10tabletsperblisterstrips.

Cartonscontaining3or10blisterstrips(30or100tablets)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/106/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5November2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 28/04/2011 CRN 2084410 page number: 10