DUODOPA

Main information

  • Trade name:
  • DUODOPA Gel 20/5 Mg/Ml
  • Dosage:
  • 20/5 Mg/Ml
  • Pharmaceutical form:
  • Gel
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DUODOPA Gel 20/5 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0410/005/001
  • Authorization date:
  • 18-11-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Duodopa,20mg/ml+5mg/ml,intestinalgel

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlcontains20mglevodopaand5mgcarbidopamonohydrate.

100mlcontain2000mglevodopaand500mgcarbidopamonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Intestinalgel.

Whitetoslightlyyellowgel.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedlevodopa-responsiveParkinson’sdiseasewithseveremotorfluctuationsandhyper-/dyskinesia

whenavailablecombinationsofParkinsonmedicinalproductshavenotgivensatisfactoryresults.

ApositivetestoftheclinicalresponsetoDuodopaadministeredviaatemporarynasoduodenaltubeisrequiredbeforea

permanenttubeisinserted.

4.2Posologyandmethodofadministration

Duodopaisagelforcontinuousintestinaladministration.Forlong-termadministration,thegelshouldbeadministered

withaportablepumpdirectlyintotheduodenumorupperjejunumbyapermanenttubeviapercutaneousendoscopic

gastrostomywithanoutertransabdominaltubeandaninnerintestinaltube.Alternatively,aradiological

gastrojejunostomymaybeconsideredifpercutaneousendoscopicgastrostomyisnotsuitableforanyreason.

Establishmentofthetransabdominalportanddoseadjustmentsshouldbecarriedoutinassociationwithaneurological

clinic.

Atemporarynasoduodenaltubeisrecommendedtofindoutifthepatientrespondsfavourablytothismethodof

treatmentandtoadjustthedosebeforetreatmentwithapermanenttubeisstarted.

Thedoseshouldbeadjustedtoanoptimalclinicalresponsefortheindividualpatient,whichmeansmaximizingthe

functionalON-timeduringthedaybyminimizingthenumberofOFFepisodesandthetimeOFF(bradykinesia)and

minimizingON-timewithdisablingdyskinesia.

SeerecommendationsunderDosage.

Duodopashouldbegiveninitiallyasmonotherapy.IfrequiredothermedicinalproductsforParkinson'sdiseasecanbe

takenconcurrently.ForadministrationofDuodopaonlytheCADD-legacyDuodopapump(CE0473)shouldbeused.

Amanualwithinstructionsforusingtheportablepumpisdeliveredtogetherwiththepump.

TreatmentwithDuodopausingapermanenttubecanbediscontinuedatanytimebywithdrawingthetubeandletting

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Dosage:

Thetotaldose/dayofDuodopaiscomposedofthreeindividuallyadjusteddoses:themorningbolusdose,the

continuousmaintenancedoseandextrabolusdoses.

Morningdose:Themorningbolusdoseisadministeredbythepumptorapidlyachievethetherapeuticdoselevel

(within10-30minutes).Thedoseshouldbebasedonthepatient’spreviousmorningintakeoflevodopa+thevolumeto

fillthetubing.Thetotalmorningdoseisusually5-10ml,correspondingto100-200mglevodopa.Thetotalmorning

doseshouldnotexceed15ml(300mglevodopa).

Continuousmaintenancedose:Themaintenancedoseisadjustableinstepsof2mg/hour(0.1ml/hour).Thedose

shouldbecalculatedaccordingtothepatient'spreviousdailyintakeoflevodopa.Whensupplementarymedicinesare

discontinuedtheDuodopadoseshouldbeadjusted.Thecontinuousmaintenancedoseisadjustedindividually.Itshould

bekeptwithinarangeof1-10ml/hour(20-200mglevodopa/hour)andisusually2-6ml/hour(40-120mg

levodopa/hour).Themaximumrecommendeddailydoseis200ml(seesection4.4).Inexceptionalcasesahigherdose

maybeneeded.

Example:

DailyintakeoflevodopaasDuodopa:1640mg/day

Morningbolusdose:140mg=7ml(excludingthevolumetofilltheintestinaltube)

Continuousmaintenancedose:1500mg/day

1500mg/day:20mg/ml=75mlDuodopaperday

Theintakeiscalculatedover16hours:75ml/16hours=4.7ml/hour.

Extrabolusdoses:Tobegivenasrequiredifthepatientbecomeshypokineticduringtheday.Theextradoseshouldbe

adjustedindividually,normally0.5-2.0ml.Inrarecasesahigherdosemaybeneeded.Iftheneedforextrabolusdoses

exceeds5perdaythemaintenancedoseshouldbeincreased.

Aftertheinitialdosesetting,fineadjustmentsofthemorningbolusdose,themaintenancedoseandextrabolusdoses

shouldbecarriedoutoverafewweeks.

IfmedicallyjustifiedDuodopamaybeadministeredduringthenight.

Monitoringoftreatment:Asuddendeteriorationintreatmentresponsewithrecurringmotorfluctuationsshouldleadto

thesuspicionthatthedistalpartofthetubehasbecomedisplacedfromtheduodenumintothestomach.Thelocationof

thetubeshouldbedeterminedbyX-rayandtheendofthetuberepositionedtotheduodenumunderradiological

control.

Paediatricpopulation

ThereisnorelevantindicationforuseofDuodopainchildrenandadolescents.

GeriatricPopulation

Thereisaconsiderableexperienceintheuseoflevodopa/carbidopainelderlypatients.Thedosagerecommendations

setoutabovereflecttheclinicaldataderivedfromthisexperience.

Renal/hepaticimpairment

Nodoseadjustmentisnecessary.

Interruptionoftherapy

Patientsshouldbecarefullyobservedincaseasuddenreductionofthedoseisrequiredorifitbecomesnecessaryto

discontinuetreatmentwithDuodopa,particularlyifthepatientisreceivingantipsychotics,seesection4.4.

Inthecaseofsuspectedordiagnoseddementiawithadecreasedconfusionthreshold,thepumpofthepatientshouldbe

handledonlybythenursingstafforacloserelativecapableofdoingso.

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nasoduodenaltubeorthetransabdominalport/duodenaltubeforadministration,accordingtotheinstructionsgiven.

Thedrugcassettesareforsingleuseonlyandshouldnotbeusedforlongerthanoneday(upto16hours)evenifsome

medicinalproductremains.Donotreuseanopenedcassette.

Bytheendofthestoragetimethegelmightbecomeslightlyyellow.Thisdoesnotinfluencetheconcentrationofthe

drugorthetreatment.

4.3Contraindications

Duodopaiscontraindicatedinpatientswith:

hypersensitivitytolevodopa,carbidopaoranyoftheexcipients

narrow-angleglaucoma

severeliverandrenalinsufficiency

severeheartfailure

severecardiacarrhythmia

acutestroke

Non-selectiveMAOinhibitorsandselectiveMAOtypeAinhibitorsmustnotbegivenconcomitantly,andshould

bewithdrawnatleasttwoweeksbeforeinitiationofDuodopa,seesection4.5.

Conditionsinwhichadrenergicsarecontraindicated,e.g.pheochromocytoma,hyperthyroidismandCushing’s

syndrome.

4.4Specialwarningsandprecautionsforuse

Severalwarningsandprecautionsbelowaregenericforlevodopaand,therefore,alsoforDuodopa.

Duodopaisnotrecommendedforthetreatmentofdrug-inducedextrapyramidalreactions.

Duodopatherapyshouldbeadministeredwithcautiontopatientswithseverecardiovascularorpulmonary

disease,bronchialasthma,renal,hepaticorendocrinedisease,orhistoryofpepticulcerdiseaseorofconvulsions.

Inpatientswithahistoryofmyocardialinfarctionwhohaveresidualatrialnodalorventriculararrhythmias,

cardiacfunctionshouldbemonitoredwithparticularcareduringtheperiodofinitialdosageadjustments.

AllpatientstreatedwithDuodopashouldbemonitoredcarefullyforthedevelopmentofmentalchanges,

depressionwithsuicidaltendencies,andotherseriousmentalchanges.Patientswithpastorcurrentpsychosis

shouldbetreatedwithcaution.

Concomitantadministrationofantipsychoticswithdopaminereceptorblockingproperties,particularlyD2

receptorantagonistsshouldbecarriedoutwithcaution,andthepatientcarefullyobservedforlossof

antiparkinsonianeffectorworseningofparkinsoniansymptoms,seesection4.5.

Patientswithchronicwide-angleglaucomamaybetreatedwithDuodopawithcaution,providedtheintra-ocular

pressureiswellcontrolledandthepatientismonitoredcarefullyforchangesinintra-ocularpressure.

Duodopamayinduceorthostatichypotension.ThereforeDuodopashouldbegivencautiouslytopatientswhoare

takingothermedicinalproductswhichmaycauseorthostatichypotension,seesection4.5.

LevodopahasbeenassociatedwithsomnolenceandepisodesofsuddensleeponsetinpatientswithParkinson’s

diseaseandcautionshouldthereforebeexercisedwhendrivingandoperatingmachines.

AsymptomcomplexresemblingNeurolepticMalignantSyndrome(NMS),includingmuscularrigidity,

increasedbodytemperature,mentalchanges(e.g.agitation,confusion,coma)andincreasedserumcreatine

phosphokinase,hasbeenreportedwhenanti-Parkinsonianmedicinalproductswerewithdrawnabruptly.

RhabdomyolysissecondarytoNeurolepticMalignantSyndromeorseveredyskinesiashavebeenobservedrarely

inpatientswithParkinson’sdisease.Therefore,patientsshouldbecarefullyobservedwhenthedoseof

levodopa/carbidopacombinationsareabruptlyreducedordiscontinued,especiallyifthepatientisreceivinganti-

psychotics.NeitherNMSnorrhabdomyolysishasbeenreportedinassociationwithDuodopa.

Pathologicgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson´sdisease,includinglevodopa/carbidopa.

Ifgeneralanaesthesiaisrequired,treatmentwithDuodopamaybecontinuedforaslongasthepatientis

permittedtotakefluidsandmedicinalproductsbymouth.Iftherapyhastobestoppedtemporarily,Duodopaat

thesamedoseasbeforemayberestartedassoonasoralintakeoffluidisallowed.

ThedoseofDuodopamayneedtobeadjusteddownwardsinordertoavoidlevodopainduceddyskinesias.

Periodicevaluationofhepatic,haematopoietic,cardiovascularandrenalfunctionisrecommendedduring

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Duodopacontainshydrazine,adegradationproductofcarbidopathatcanbegenotoxicandpossibly

carcinogenic.TheaveragerecommendeddailydoseofDuodopais100ml,containing2glevodopaand0.5g

carbidopa.Themaximumrecommendeddailydoseis200ml.Thisincludeshydrazineatuptoanaverage

exposureof4mg/day,withamaximumof8mg/day.Theclinicalsignificanceofthishydrazineexposureisnot

known.

Previoussurgeryintheupperpartoftheabdomenmayleadtodifficultyinperforminggastrostomyor

jejunostomy

Reducedabilitytohandlethesystem(pump,tubeconnections)canleadtocomplications.Insuchpatientsa

caregiver(e.g.nurse,assistantnurse,orcloserelative)shouldassistthepatient.

Asuddenorgradualworseningofbradykinesiamayindicateanobstructioninthedeviceforwhateverreason

andneedstobeexplored.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

NointeractionstudieshavebeenperformedwithDuodopa.Thefollowinginteractionsareknownfromthegeneric

combinationoflevodopa/carbidopa.

CautionisneededinconcomitantadministrationofDuodopawiththefollowingmedicinalproducts:

Antihypertensives

Symptomaticposturalhypotensionhasoccurredwhencombinationsoflevodopaandadecarboxylaseinhibitorare

addedtothetreatmentofpatientsalreadyreceivinganti-hypertensives.Dosageadjustmentoftheantihypertensive

agentmayberequired.

Antidepressants

Therehavebeenrarereportsofadversereactions,includinghypertensionanddyskinesia,resultingfromthe

concomitantadministrationoftricyclicantidepressantsandcarbidopa/levodopapreparations,seesection4.3.

Anticholinergics

Anticholinergicsmayactsynergisticallywithlevodopatodecreasetremor.However,combinedusemayexacerbate

abnormalinvoluntarymovements.Anticholinergicsmaydecreasetheeffectsoflevodopabydelayingitsabsorption.

AnadjustmentofthedoseofDuodopamaybeneeded.

COMTinhibitors(tolcapone,entacapone)

ConcomitantuseofCOMT(Catechol-O-MethylTransferase)inhibitorsandDuodopacanincreasethebioavailability

oflevodopa.ThedoseofDuodopamayneedadjustment.

Othermedicinalproducts

Dopaminereceptorantagonists(someantipsychotics,e.g.phenothiazines,butyrophenonsandrisperidoneand

antiemetics,e.g.metoclopramide),benzodiazepines,isoniazide,phenytoinandpapaverinecanreducethetherapeutic

effectoflevodopa.PatientstakingthesemedicinalproductstogetherwithDuodopashouldbeobservedcarefullyfor

lossoftherapeuticresponse.

DuodopacanbetakenconcomitantlywiththerecommendeddoseofanMAOinhibitor,whichisselectiveforMAO

typeB(forinstanceselegiline-HCl).

Concomitantuseofselegilineandlevodopa-carbidopahasbeenassociatedwithseriousorthostatichypotension.

Amantadinehassynergiceffectwithlevodopaandmayincreaselevodoparelatedadverseevents.Anadjustmentofthe

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Sympathicomimeticsmayincreasecardiovascularadverseeventsrelatedtolevodopa.

Levodopaformsachelatewithironinthegastrointestinaltractleadingtoreducedabsorptionoflevodopa.

Aslevodopaiscompetitivewithcertainaminoacids,theabsorptionoflevodopacanbedisturbedinpatientswhoare

onaproteinrichdiet.

TheeffectofadministrationofantacidsandDuodopaonthebioavailabilityoflevodopahasnotbeenstudied.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoflevodopa/carbidopainpregnantwomen.Datafromanimalstudieshave

shownreproductiontoxicity,seesection5.3.Thepotentialriskforhumansisunknown.Duodopashouldnotbeused

duringpregnancyunlessthebenefitsforthemotheroutweighthepossibleriskstothefoetus.

Lactation

Levodopaisexcretedinthebreastmilk.Thereisevidencethatlactationissuppressedduringtreatmentwithlevodopa.

Itisunknownwhethercarbidopaisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionofcarbidopa

inbreastmilk.Thesafetyoflevodopaandcarbidopaintheinfantisnotknown.Duodopashouldnotbeusedduring

breast-feeding.

4.7Effectsonabilitytodriveandusemachines

Levodopaandcarbidopamaycausedizzinessandorthostatichypotension.Therefore,cautionshouldbeexercisedwhen

drivingorusingmachines.PatientsbeingtreatedwithDuodopaandpresentingwithsomnolenceand/orsuddensleep

episodesmustbeadvisedtorefrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthem,or

others,atriskofseriousinjuryordeath(e.g.operatingmachines)untilsuchrecurrentepisodesandsomnolencehave

resolved,seealsosection4.4.

4.8Undesirableeffects

Undesirableeffectsthatoccurfrequentlywithlevodopa/carbidopaarethoseduetocentralneuropharmacological

activityofdopamine.Thesereactionscanusuallybediminishedbylevodopadosagereduction.

MedDRAsystem

organclass Common

1/100,<1/10 Uncommon

1/1,000,<1/100 Rare

1/10,000,<1/1,000 Veryrare

<1/10,000

Bloodandlymphatic

systemdisorders Leucopenia,

haemolyticandnon-

haemolyticanaemia,

thrombocytopenia Agranulocytosis

Metabolismand

nutritiondisorders Anorexia Lossofweight,

increasedweight

Psychiatricdisorders Hallucinations,

confusion,nightmares,

sleepiness,fatigue,

sleeplessness,

depressionwithvery

raresuicideattempts,

euphoria,dementia,

psychoticepisodes,

feelingofstimulation Agitation,fear,

reducedthinking

capacity,

disorientation,

increasedlibido,

numbness

Nervoussystem

disorders Dyskinesias,choreatic

movementsand

dystonia,“ON-OFF”

episodes,dizziness,

bradykinesia(“ON-

OFF”episodes)[1],

somnolence[2] Ataxia,increased

tremorofthehands Neurolepticmalignant

syndrome,

paraesthesias,falling,

walkingdefects,

trismus,headache,

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Bradykinesia(“ON-OFF”episodes)mayappearsomemonthstoyearsafterthebeginningoftreatmentwithlevodopaandisprobably

relatedtotheprogressionofthedisease.Theadaptionofdosescheduleanddoseintervalsmayberequired.

Levodopa/carbidopaisassociatedwithsomnolenceandhasbeenassociatedveryrarelywithexcessivedaytimesomnolenceandsudden

sleeponsetepisodes.

Otheradversereactionshavebeenreportedinassociationwithlevodopa/carbidopacombinationsincludingDuodopa:

PatientstreatedwithdopamineagonistsfortreatmentofParkinson´sdisease,includinglevodopa/carbidopa,especially

athighdoses,havebeenreportedasshowingpathologicalgambling,increasedlibidoandhypersexuality,generally

reversibleuponreductionofthedoseortreatmentdiscontinuation.

Laboratoryvalues:Thefollowinglaboratoryabnormalitieshavebeenreportedwithlevodopa/carbidopatreatmentand

should,therefore,beacknowledgedwhentreatingpatientswithDuodopa:elevatedureanitrogen,alkaline

phosphatases,S-AST,S-ALT,LDH,bilirubin,bloodsugar,creatinine,uricacidandpositiveCoomb’stest,and

loweredvaluesofhaemoglobinandhaematocrit.Leucocytes,bacteriaandbloodintheurinehavebeenreported.

Levodopa/carbidopa,andthusDuodopa,maycauseafalsepositiveresultwhenadipstickisusedtotestforurinary

ketone;thisreactionisnotalteredbyboilingtheurinesample.Theuseofglucoseoxidasemethodsmaygivefalse

negativeresultsforglucosuria.

Eyedisorders Blurredvision,

blepharospasm(see

section4.9),activation

ofalatentHorner’s

syndrome,double

vision,dilatedpupils,

oculogyriccrises

Cardiacdisorders Palpitations,irregular

heartbeat

Vasculardisorders Orthostatic

hypotension,

inclinationtofaint,

syncope Hypertension Phlebitis

Respiratory,thoracic

andmedastinal

disorders Hoarseness,chestpain Dyspnoea,abnormal

breathingpattern

Gastrointestinal

disorders Nausea,vomiting,dry

mouth,bittertaste Constipation,diarrhea,

sialorrhoea.

Dysphagia,flatulence Dyspepsia,

gastrointestinalpain,

darksaliva,bruxism,

hiccups,

gastrointestinal

bleeding,burning

sensationofthe

tongue,duodenal

ulceration

Skinand

subcutaneoustissue

disorders Oedema Angiooedema,

urticaria,pruritus,

facialredness,hair

loss,exanthema,

increasedperspiration,

darkperspirationfluid,

malignantmelanoma,

Schönlein-Henoch

purpura

Musculoskeletal,

connectivetissueand

bonedisorders Musclespasms

Renalandurinary

disorders Darkurine Urinaryretention,

urinaryincontinence,

priapism

Generaldisorders

andadministration

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intestinaltube.Dislocationoftheintestinaltubebackwardsintothestomachleadstoreappearanceofmotor

fluctuations(duetoerraticgastricemptyingofDuodopaintothesmallintestines).Ingeneral,relocationofthetubecan

bedoneusingaguide-wiretosteerthetubeintotheduodenumunderfluoroscopy.Occlusion,kinks,orknotsofthe

intestinaltubeleadtohighpressuresignalsfromthepump.Occlusionsareusuallyremediedbyflushingthetubewith

tapwater;kinking,knotting,oratubedisplacementmayneedreadjustmentofthetubing.Shouldcompletefailureof

theintestinaltubeorpumpoccurthepatientmustbetreatedwithorallevodopa/carbidopauntiltheproblemissolved.

Thestomausuallyhealswithoutcomplications.However,abdominalpain,infectionandleakageofgastricfluidmay

occurshortlyaftersurgery;itisrarelyaproblemlong-term.Reportedcomplicationsincludeperforationofadjacent

anatomicalstructuresespeciallyduringPEGplacementandbleeding,woundinfection(themostcommon

complication)andperitonitis.Localinfectionsaroundthestomaaretreatedconservativelywithadisinfectant.

Treatmentwithantibioticsisrarelyneeded.

4.9Overdose

Mostprominentclinicalsymptomsofanoverdosewithlevodopa/carbidopaaredystoniaanddyskinesia.

Blepharospasmscanbeanearlysignofoverdose.

ThetreatmentofanacuteoverdoseofDuodopaisingeneralthesameasthatofanacuteoverdoseoflevodopa:

However,pyridoxinehasnoeffectonthereversaloftheactionofDuodopa.Electrocardiographicmonitoringshouldbe

usedandthepatientobservedcarefullyforthedevelopmentofcardiacarrhythmias;ifnecessaryanappropriate

antiarrhythmictherapyshouldbegiven.Thepossibilitythatthepatienttookothermedicinalproductstogetherwith

Duodopashouldbetakenintoconsideration.Todateexperienceswithdialysishavenotbeenreported,thereforeits

valueinthetreatmentofoverdoseisunknown.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-Parkinsondrugs,levodopaanddecarboxylaseinhibitor

ATCcode:N04BA02.

Duodopaisacombinationoflevodopaandcarbidopa(ratio4:1)inagelforcontinuousintestinalinfusioninadvanced

Parkinson’sdiseasewithseveremotorfluctuationsandhyper-/dyskinesia.LevodoparelievessymptomsofParkinson’s

diseasefollowingdecarboxylationtodopamineinthebrain.Carbidopa,whichdoesnotcrosstheblood-brainbarrier,

inhibitstheextracerebraldecarboxylationoflevodopa,whichmeansthatalargeramountoflevodopabecomes

availablefortransportationtothebrainandtransformationintodopamine.Withoutthesimultaneousadministrationof

carbidopamuchlargeramountsoflevodopawouldberequiredtoachievethedesiredeffect.

IntestinaltherapywithDuodopareducesthemotorfluctuationsandincreasesthe”ON”-timeforpatientswithadvanced

Parkinson’sdiseasewhohavereceivedtablettreatmentwithlevodopa/decarboxylaseinhibitorformanyyears.The

motorfluctuationsandhyper-/dyskinesiasarereducedduetothefactthattheplasmaconcentrationsoflevodopaare

beingkeptatasteadylevelwithintheindividualtherapeuticwindow.Therapeuticeffectsonmotorfluctuationsand

hyper-/dyskinesiasareoftenachievedduringthefirsttreatmentday.

5.2Pharmacokineticproperties

Absorption

Duodopaisadministeredviaaninsertedtubedirectlyintotheduodenum.Levodopaisabsorbedquicklyandeffectively

fromtheintestinethroughahighcapacitytransportsystemforaminoacids.LevodopagivenasDuodopahasthesame

bioavailabilityaslevodopagivenastablets(81-98%).Thevariationinplasmaconcentrationwithinanindividualis

considerablysmallerforDuodopaduetothefactthatitisgivenbycontinuousintestinaladministrationinwhichthe

gastricemptyingratehasnoinfluenceontheabsorptionrate.WithaninitialhighmorningdoseofDuodopathe

therapeuticplasmaleveloflevodopaisreachedwithin10-30minutes.

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Levodopaisco-administeredwithcarbidopa,adecarboxylaseinhibitor,whichincreasesthebioavailabilityand

decreasesclearanceforlevodopa.Clearanceandvolumeofdistributionforlevodopais0.3l/hour/kgand0.9-1.6l/kg,

respectively,whengiventogetherwithadecarboxylaseinhibitor.Theproteinbindingoflevodopainplasmais

negligible.

Metabolismandelimination

Theeliminationhalf-lifeforlevodopaisapproximately1-2hours.Levodopaiseliminatedcompletelythrough

metabolismandthemetabolitesformedareexcretedmainlyintheurine.Fourmetabolicpathwaysareknown,

decarboxylationbeingpredominantforlevodopaadministeredwithoutanyenzymeinhibitor.Whenlevodopaisco-

administeredwithcarbidopathedecarboxylaseenzymeisinhibitedsothatmetabolismviacatechol-O-methyl-

transferase(COMT)becomesthedominantmetabolicpathway.

Pharmacokinetic-pharmacodynamicrelationship

Thereducedfluctuationsintheplasmaconcentrationoflevodopareducefluctuationsinthetreatmentresponse.The

levodopadoseneededvariesconsiderablyinadvancedParkinson’sdiseaseanditisimportantthatthedoseis

individuallyadjustedbasedontheclinicalresponse.Developmentoftoleranceovertimehasnotbeenobservedwith

Duodopa.Onthecontrary,manypatients,afteraperiodofsatisfactorytreatmentwithDuodopa,mayfindthatalower

doseoflevodopawillprovideasatisfactoryclinicalresponse.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafety,pharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential,toxicitytoreproduction.Inreproductivetoxicitystudiesboth

levodopaandthecombinationofcarbidopa/levodopahavecausedvisceralandskeletalmalformationsinrabbits.

HydrazineisadegradationproductofCarbidopa.Inanimalstudies,hydrazineshowednotablesystemictoxicity,

particularlybyinhalationexposure.Thesestudiesreportedthathydrazineishepatotoxic,hasCNStoxicities(although

notdescribedafteroraltreatment),andisgenotoxicaswellascarcinogenic(seealsosection4.4).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosesodium

PurifiedWater

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Unopened:15weeks.

Onceopened:Useimmediately.Discardanyunusedportion.

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6.4Specialprecautionsforstorage

Storeinarefrigerator(2ºC-8°C).

Keepthecassetteintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Totalamountof100mlinPVCbaginsideahardplasticcassetteforprotection,cartonwith7cassettes.

6.6Specialprecautionsfordisposalandotherhandling

Cassettesareforsingleuseonly.

Donotre-useanopenedcassette.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

Empty/usedcassettesshouldbereturnedtothepharmacyfordestruction.

7MARKETINGAUTHORISATIONHOLDER

AbbottProductsGmbH

Hans-Boeckler-Allee20

D-30173Hannover

Germany

8MARKETINGAUTHORISATIONNUMBER

PA410/5/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18November2005

Dateoflastrenewal:21January2009

10DATEOFREVISIONOFTHETEXT

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