APOMORPHINE HYDROCHLORIDE

Main information

  • Trade name:
  • APOMORPHINE HYDROCHLORIDE
  • Dosage:
  • 10 Mg/Ml
  • Pharmaceutical form:
  • Solution for Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • APOMORPHINE HYDROCHLORIDE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0757/008/001
  • Authorization date:
  • 05-02-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Apomorphinehydrochloride10mg/mlsolutionforinjection/infusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains10mgapomorphinehydrochloride

2mlcontains20mgapomorphinehydrochloride

5mlcontains50mgapomorphinehydrochloride

Sodiummetabisulphite1mg/ml

Sodium0.3mg/ml(maximum)

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Solutionforinjection/infusion

Aclear,colourlesstopaleyellowsolution.pH3–4

4CLINICALPARTICULARS

4.1TherapeuticIndications

Thetreatmentofdisablingmotorfluctuations(“on-off”phenomena)inpatientswithParkinson'sdiseasewhichpersist

despiteindividuallytitratedtreatmentwithlevodopa(withaperipheraldecarboxylaseinhibitor)and/orotherdopamine

agonists.

4.2Posologyandmethodofadministration

Apomorphine10mg/mlsolutionforinjectionisforsubcutaneoususebyintermittentbolusinjection.Apomorphine

10mg/mlsolutionforinjectionmayalsobeadministeredasacontinuoussubcutaneousinfusionbyminipumpand/or

syringedriver.Apomorphine10mg/mlsolutionforinjectionmaybedilutedwithsodiumchloride9mg/ml(0.9%)

solutionforinjectionorWaterforInjections.

Apomorphinemustnotbeusedviatheintravenousroute.

Dosage

Adults

Administration

Selectionofpatientssuitableforapomorphine10mg/mlsolutionforinjection

PatientsselectedfortreatmentwithApomorphine10mg/mlsolutionforinjectionshouldbeabletorecognisetheonset

oftheir‘off’symptomsandbecapableofinjectingthemselvesorelsehavearesponsiblecarerabletoinjectforthem

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Itisessentialthatthepatientisestablishedondomperidone,usually20mgthreetimesdailyforatleasttwodaysprior

toinitiationoftherapy.

Apomorphineshouldbeinitiatedinthecontrolledenvironmentofaspecialistclinic.Thepatientshouldbesupervised

byaphysicianexperiencedinthetreatmentofParkinson’sdisease(e.g.neurologist).Thepatient’streatmentwith

levodopa,withorwithoutdopamineagonists,shouldbeoptimisedbeforestartingApomorphine10mg/mlsolutionfor

injectiontreatment.

Determinationofthethresholddose

Theappropriatedoseforeachpatientisestablishedbyincrementaldosingschedules.Thefollowingscheduleis

suggested:

1mgofapomorphineHCl(0.1ml),thatisapproximately15to20micrograms/kg,maybeinjectedsubcutaneously

duringahypokineticor‘off’periodandthepatientobservedover30minutesforamotorresponse.

Ifnoresponse,oraninadequateresponse,isobtainedaseconddoseof2mgapomorphineHCl(0.2ml)canbegiven

subcutaneouslyafteratleast40minutesandthepatientobservedforaforanadequateresponseforafurther30

minutes.

Thedosagemaybeincreasedbyincrementalinjectionswithatleasta40minuteintervalbetweensucceeding

injections,untilasatisfactorymotorresponseisobtained.

Establishmentoftreatment

Oncetheappropriatedoseisdeterminedasinglesubcutaneousinjectionmaybegivenintothelowerabdomenorouter

thighatthefirstsignsofan'off'episode.Itcannotbeexcludedthatabsorptionmaydifferwithdifferentinjectionsites

withinasingleindividual.Accordingly,thepatientshouldthenbeobservedforthenexthourtoassessthequalityof

theirresponsetotreatment.Alterationsindosagemaybemadeaccordingtothepatient'sresponse.

Theoptimaldosageofapomorphinehydrochloridevariesbetweenindividualsbut,onceestablished,remainsrelatively

constantforeachpatient.

Precautionsoncontinuingtreatment

Thedailydoseofapomorphine10mg/mlsolutionforinjectionvarieswidelybetweenpatients,typicallywithinthe

rangeof3mgto30mg,givenas1to10injectionsandsometimesasmanyas12separateinjectionsperday.

ItisrecommendedthatthetotaldailydoseofapomorphineHClshouldnotexceed100mgandthatindividualbolus

injectionsshouldnotexceed10mg.

Inclinicalstudiesithasusuallybeenpossibletomakesomereductioninthedoseoflevodopa,thiseffectvaries

considerablybetweenpatientsandneedstobecarefullymanagedbyanexperiencedphysician.

Oncetreatmenthasbeenestablisheddomperidonetherapymaybegraduallyreducedinsomepatientsbutsuccessfully

eliminatedonlyinafew,withoutanyvomitingorhypotension.

ContinuousInfusion

Patientswhohaveshownagood‘on’periodresponseduringtheinitiationstage,butwhoseoverallcontrolremains

unsatisfactoryusingintermittentinjections,orwhorequiremanyandfrequentinjections(morethan10perday),may

becommencedonortransferredtocontinuoussubcutaneousinfusionbyminipumpand/orsyringe-driverasfollows:

Continuousinfusionisstartedatarateof1mgapomorphineHCl(0.1ml)perhourthenincreasedaccordingtothe

individualresponse.Increasesintheinfusionrateshouldnotexceed0.5mgperhouratintervalsofnotlessthan4

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0.06mg/kg/hour.Infusionsshouldrunforwakinghoursonly.Unlessthepatientisexperiencingseverenight-time

problems,24hourinfusionsarenotadvised.Tolerancetothetherapydoesnotseemtooccuraslongasthereisan

overnightperiodwithouttreatmentofatleast4hours.Inanyevent,theinfusionsiteshouldbechangedevery12hours.

Theabovevolumesareforundilutedapomorphinehydrochloride10mg/ml.Volumesmustbeadjustedtoallowfor

dilutionundertakenpriortouse.

Patientsmayneedtosupplementtheircontinuousinfusionwithintermittentbolusboostsviathepumpsystemas

necessary,andasdirectedbytheirphysician.

Areductionindosageofotherdopamineagonistsmaybeconsideredduringcontinuousinfusion.

Childrenandadolescents

Apomorphine10mg/mlsolutionforinjectioniscontraindicatedforchildrenandadolescentsupto18yearsofage(see

section4.3).

Elderly

TheelderlyarewellrepresentedinthepopulationofpatientswithParkinson’sdiseaseandconstituteahighproportion

ofthosestudiedinclinicaltrialsofapomorphine.Themanagementofelderlypatientstreatedwithapomorphinehasnot

differedfromthatofyoungerpatients.

RenalImpairment

Adoseschedulesimilartothatrecommendedforadults,andtheelderly,canbefollowedforpatientswithrenal

impairment(seeSection4.4).

4.3Contraindications

Inpatientswithrespiratorydepression,dementia,psychoticdiseasesorhepaticinsufficiency.

Intermittentapomorphinetreatmentisnotsuitableforpatientswhohavean‘on’responsetolevodopathatismarredby

severedyskinesiaordystonia.

Apomorphine10mg/mlsolutionforinjectionshouldnotbeadministeredtopatientswhohaveaknownsensitivityto

apomorphineoranyoftheotheringredientsoftheproduct.

Apomorphineiscontra-indicatedinchildrenandadolescentsunder18yearsofage.

4.4Specialwarningsandprecautionsforuse

Apomorphineshouldbegivenwithcautiontopatientswithrenal,pulmonaryorcardiovasculardiseaseandpersons

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Extracautionisrecommendedduringinitiationoftherapyinelderlyand/ordebilitatedpatients.

Sinceapomorphine,especiallyathighdose,mayhavethepotentialforQTprolongation,cautionshouldbeexercised

whentreatingpatientsatriskfortorsadesdepointesarrhythmia.

Sinceapomorphinemayproducehypotension,evenwhengivenwithdomperidonepre-treatment,careshouldbe

exercisedinpatientswithpre-existingcardiacdiseaseorinpatientstakingvasoactivemedicinalproductssuchas

antihypertensives,andespeciallyinpatientswithpre-existingposturalhypotension.

Apomorphineisassociatedwithlocalsubcutaneouseffects.Thesecansometimesbereducedbytherotationof

injectionsitesorpossiblybytheuseofultrasound(ifavailable)toareasofnodularityandinduration.

Apomorphine10mg/mlsolutionforinjectioncontainssodiummetabisulphitewhichmayrarelycausesevere

hypersensitivityreactionsandbronchospasm.Italsocontainssodiumatlessthan1mmol(23mg)perml,i.e.essentially

‘sodium-free’.

Haemolyticanaemiahasbeenreportedinpatientstreatedwithlevodopaandapomorphine.Haematologytestsshould

beundertakenatregularintervalsaswithlevodopawhengivenconcomitantlywithapomorphine.

Cautionisadvisedwhencombiningapomorphinewithothermedicinalproducts,especiallythosewithanarrow

therapeuticrange(seesection4.5)

Neuropsychiatricproblemsco-existinmanypatientswithadvancedParkinson’sdisease.Thereisevidencethatfor

somepatients,neuropsychiatricdisturbancesmaybeexacerbatedbyapomorphine.Specialcareshouldbeexercised

whenapomorphineisusedinthesepatients.

Apomorphinehasbeenassociatedwithsomnolence,andotherdopamineagonistscanbeassociatedwithsuddensleep

onsetepisodes,particularlyinpatientswithParkinson’sdisease.Patientsmustbeinformedofthisandadvisedto

exercisecautionwhiledrivingoroperatingmachinesduringtreatmentwithapomorphine.Patientswhohave

experiencedsomnolencemustrefrainfromdrivingoroperatingmachines.Furthermoreareductionofdosageor

terminationoftherapymaybeconsidered.

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinpatientstreatedwithdopamine

agonistsforParkinson'sdisease,includingapomorphine.

CAUTION:Apomorphineshouldnotbespilledonclothingorhouseholdsurfacesandtextilesasspillagesmayturn

green.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ItisrecommendedtoavoidtheadministrationofapomorphinewithotherdrugsknowntoprolongtheQTinterval.

Patientsselectedfortreatmentwithapomorphinearealmostcertaintobetakingconcomitantmedicationsfortheir

Parkinson’sdisease.Intheinitialstagesofapomorphinetherapy,thepatientshouldbemonitoredforunusualside-

effectsorsignsofpotentiationofeffect.

Neurolepticmedicinalproductsmayhaveanantagonisticeffectifusedwithapomorphine.Thereisapotential

interactionbetweenclozapineandapomorphine,howeverclozapinemayalsobeusedtoreducethesymptomsof

neuropsychiatriccomplications.

IfneurolepticmedicinalproductshavetobeusedinpatientswithParkinson’sdiseasetreatedbydopamineagonists,a

gradualreductioninapomorphinedosemaybeconsideredwhenadministrationisbyminipumpand/orsyringe-driver

(symptomssuggestiveofneurolepticmalignantsyndromehavebeenreportedrarelywithabruptwithdrawalof

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4.6Fertility,pregnancyandlactation

Pregnancy

Thereisnoexperienceofapomorphineusageinpregnantwomen.

Animalreproductionstudiesdonotindicateanyteratrogeniceffects,butdosesgiventoratswhicharetoxictothe

mothercanleadtofailuretobreatheinthenewborn.Thepotentialriskforhumansisunknown(seesection5.3).

Apomorphinehydrochlorideshouldnotbeusedduringpregnancyunlessclearlynecessary.

Lactation

Itisnotknownwhetherapomorphineisexcretedinbreastmilk.Adecisiononwhethertocontinue/discontinue

breastfeedingortocontinue/discontinuetherapywithapomorphineshouldbemadetakingintoaccountthebenefitof

breast-feedingtothechildandthebenefitofapomorphinetothewoman.

4.7Effectsonabilitytodriveandusemachines

Patientsbeingtreatedwithapomorphineandpresentingwithsomnolenceand/orsuddensleepepisodesmustbe

informedtorefrainfromdrivingorengaginginactivities(e.g.operatingmachines)whereimpairedalertnessmayput

themselvesorothersatriskofseriousinjuryordeathuntilsuchrecurrentepisodesandsomnolencehaveresolved(see

section4.4).

4.8Undesirableeffects

Verycommon(1/10)

Common(1/1000to<1/10)

Uncommon(1/1000to<1/100)

Rare(1/10,000to<1/1000)

Veryrare(<1/10,000)

Notknown(cannotbeestimatedfromavailabledata.

Systemorganclass Frequency Adverseevent

Bloodandlymphatic

systemdisorders Uncommon: Haemolyticanaemiaand

thrombocytopeniahavebeen

reportedinpatientstreated

withapomorphine.

Rare: Eosinophiliahasrarely

occurredduringtreatment

withapomorphineHCl.

Immunesystem

disorders Rare: Duetothepresenceof

sodiummetabisulphite,

allergicreactions(including

anaphylaxisand

bronchospasm)mayoccur.

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disturbancesarecommonin

parkinsonianpatients.

Apomorphineshouldbeused

withspecialcautioninthese

patients.Neuropsychiatric

disturbances(including

transientmildconfusionand

visualhallucinations)have

occurredduringapomorphine

HCltherapy.

Notknown: Patientstreatedwith

dopamineagonistsfor

treatmentofParkinson's

disease,including

apomorphine,especiallyat

highdoses,havebeen

reportedasexhibitingsigns

ofpathologicalgambling,

increasedlibidoand

hypersexuality;generally

reversibleuponreductionof

thedoseortreatment

discontinuation.

Nervoussystem

disorders Common: Transientsedationwitheach

doseofapomorphineHClat

thestartoftherapymay

occur;thisusuallyresolves

overthefirstfewweeks.

Apomorphineisassociated

withsomnolence.

Dizziness/light-headedness

havealsobeenreported.

Uncommon: Apomorphinemayinduce

dyskinesiasduring'on'

periods,whichcanbesevere

insomecases,andinafew

patientsmayresultin

cessationoftherapy.

Vasculardisorders Uncommon: Posturalhypotensionisseen

infrequentlyandisusually

transient(SeeSection4.4).

Respiratory,thoracic

andmediastinal

disorders Common: Yawninghasbeenreported

duringapomorphinetherapy.

Uncommon: Breathingdifficultieshave

beenreported.

Gastrointestinal

disorders Common: Nauseaandvomiting,

particularlywhen

apomorphinetreatmentisfirst

initiated,usuallyasaresultof

theomissionofdomperidone

(SeeSection4.2).

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4.9Overdose

Thereislittleclinicalexperienceofoverdosagewithapomorphinebythisrouteofadministration.Symptomsof

overdosagemaybetreatedempiricallyassuggestedbelow:

Excessiveemesismaybetreatedwithdomperidone

Respiratorydepressionmaybetreatedwithnaloxone.

Hypotension:appropriatemeasuresshouldbetaken,e.g.raisingthefootofthebed.

Bradycardiamaybetreatedwithatropine.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Dopaminergicagents;dopamineagonists

ATCClassification:N04BC07

ApomorphineisadirectstimulantofdopaminereceptorsandwhilepossessingbothD1andD2receptoragonist

propertiesdoesnotsharetransportormetabolicpathwayswithlevodopa.

Althoughinintactexperimentalanimals,administrationofapomorphinesuppressestherateoffiringofnigro-striatal

cellsandinlowdosehasbeenfoundtoproduceareductioninlocomotoractivity(thoughttorepresentpre-synaptic

inhibitionofendogenousdopaminerelease),itsactionsonParkinsonianmotordisabilityarelikelytobemediatedat

tissuedisorders havebeenreported.

Generaldisordersand

administrationsite

conditions Verycommon: Mostpatientsexperience

injectionsitereactions,

particularlywithcontinuous

use.Thesemayinclude

subcutaneousnodules,

induration,erythema,

tendernessandpanniculitis.

Variousotherlocalreactions

(suchasirritation,itching,

bruisingandpain)mayalso

occur.

Uncommon: Injectionsitenecrosisand

ulcerationhavebeenreported.

NotKnown: Peripheraloedemahasbeen

reported.

Investigations Uncommon: PositiveCoombs'testshave

beenreportedforpatients

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5.2Pharmacokineticproperties

Apomorphine,apotentagonist,hasbeenusedinacuteandchronicstudiesofParkinsonismandotherneurological

disorders.Aftersubcutaneousinjectionitsfatecanbedescribedbyatwo-compartmentmodel,withadistributionhalf-

lifeof5(±1.1)minutesandaneliminationhalf-lifeof33(±3.9)minutes.Clinicalresponsecorrelateswellwithlevels

ofapomorphineinthecerebrospinalfluid.Fromthedrugabsorption,volumeofinjection,S.C.infusion,andI.V.

infusion,itcanbeconcludedthatapomorphineisrapidlyandcompletelyabsorbedfromsubcutaneoustissue,

correlatingwiththerapidonsetofclinicaleffects(4to12minutes),andthatthebriefdurationofaclinicalactionofthe

drug(about1hour)isexplainedbyitsrapidclearance.

Themetabolismofapomorphineisbyglucurondationandsulphonationtoatleasttenpercentofthetotal;other

pathwayshavenotbeendescribed.

5.3Preclinicalsafetydata

Repeatdosesubcutaneoustoxicitystudiesrevealnospecialhazardforhumans,beyondtheinformationincludedin

othersectionsoftheSummaryofProductCharacteristics.

Invitrogenotoxicitystudiesdemonstratedmutagenicandclastogeniceffects,mostlikelyduetoproductsformedby

oxidationofapomorphine.However,apomorphinewasnotgenotoxicintheinvivostudiesperformed.

Theeffectofapomorphineonreproductionhasbeeninvestigatedinrats.Apomorphinewasnotteratogenicinthis

species,butitwasnotedthatdoseswhicharetoxictothemothercancauselossofmaternalcareandfailuretobreathe

inthenewborn.Nocarcinogenicitystudieshavebeenperformed.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiummetabisulphite(E223)

Hydrochloricacid(37%)forpHadjustment

Sodiumhydroxide(99%)forpHadjustment

WaterforInjections

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Unopened:2years

Shelflifeafterfirstopeningtheampoule:Immediateuse

Shelflifeafterdilution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat2-8°Cand25°Cwhentheproductis

dilutedwithsodiumchloride0.9%injectionorWaterforInjectionsinpolypropylenesyringes.Fromamicrobiological

pointofviewtheproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditions

priortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2ºCto8°C,unless

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6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keeptheampoulesintheoutercarton,inordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Clear,colourlesstypeIglassampoulescontaining2mlsolutionforinjection,suppliedinpacksof5or10ampoules.

Clear,colourlesstypeIglassampoulescontaining5mlsolutionforinjection,suppliedinpacksof5or10ampoules.

Bundlepackof25and50ampoulesareavailableinsomecountries.

The25ampoulepackconsistsof5packseachcontaining

5ampoules.

The50ampoulepackconsistsof10packseachcontaining

5ampoules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Donotuseifthesolutionhasturnedgreen.Thesolutionshouldbeinspectedvisuallypriortouse.Onlyclear,

colourlesstopaleyellowsolutionsshouldbeused.

Forsingleuseonly.Anyunusedsolutionshouldbediscarded

Apomorphine10mg/mlsolutionforinjectioniscompatiblewithsodiumchloridesolution9mg/ml(0.9%)solutionfor

injectionandWaterforInjection.

7MARKETINGAUTHORISATIONHOLDER

ArchimedesPharmaUKLimited

250SouthOakWay

GreenPark

Reading

BerkshireRG26UG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA757/8/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5thFebruary2010

10DATEOFREVISIONOFTHETEXT

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