CLOPIXOL ACUPHASE

Main information

  • Trade name:
  • CLOPIXOL ACUPHASE
  • Dosage:
  • 50 Mg/ Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLOPIXOL ACUPHASE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0115/005/009
  • Authorization date:
  • 08-10-1990
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClopixolAcuphase50mg/mlSolutionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachampoulecontainszuclopenthixolacetate50mgin1mlofinjectionfluid.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjection(injection)

Clear,yellowish,oil,practicallyfreefromparticles.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Initialtreatmentofacutepsychosesincludingmaniaandexacerbationofchronicpsychoses.

4.2Posologyandmethodofadministration

Adults

Dosageshouldbeindividuallyadjustedaccordingtotheconditionofthepatient.

Thedoserangewouldnormallybe50-150mg(1-3ml)i.m.,repeatedifnecessary,preferablywithatimeintervalof

twoortheedays.Inafewpatientsanadditionalinjectionmaybeneeded24to48hoursafterthefirstinjection.

Zuclopenthixolacetateisnotintendedforlong-termuseanddurationoftreatmentshouldnotbemorethantwoweeks.

Themaximumaccumulateddosageinacourseshouldnotexceed400mgandthenumberofinjectionsshouldnot

exceedfour.

Inthemaintenancetherapy,treatmentshouldbecontinuedwithoralzuclopenthixolorzuclopenthixoldecanoatei.m.,

accordingtothefollowingguidelines:

1)Changetooralzuclopenthixol

Twotothreedaysafterthelastinjectionofzuclopenthixolacetateapatientwhohasbeentreatedwith100mg

zuclopenthixolacetate,shouldbestartedatanoraldosageofabout40mgdaily,possiblyindivideddosages.Ifnecessary

thedosecanbefurtherincreasedby10-20mgeverytwotothreedaysupto75mgdailyormore.

2)Changetozuclopenthixoldecanoate

Concomitantlywiththe(last)injectionofzuclopenthixolacetate(100mg),200-400mg(1-2ml)ofzuclopenthixol

decanoate200mg/mlshouldbegivenintramuscularlyandrepeatedevery2ndweek.Higherdosesorshorterintervalsmay

beneeded.

Zuclopenthixolacetateandzuclopenthixoldecanoatecanbemixedinasyringeandgivenasoneinjection(co-injection).

Subsequentdosesofzuclopenthixoldecanoateandintervalbetweeninjectionsshouldbeadjustedaccordingtothe

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Elderly

Thedosagemayneedtobereducedintheelderly.Maximumdosageperinjectionshouldbe100mg.

Children

ClopixolAcuphaseisnotrecommendedforuseinchildrenduetolackofclinicalexperience.

Reducedrenalfunction

ClopixolAcuphasecanbegiveninusualdosestopatientswithreducedrenalfunction.

Reducedhepaticfunction

Dosereduction(relativetothedegreeofhepaticimpairment)shouldbeconsidered.Ifpossible,whereassayfacilitiesexist

dosageshouldbeadjustedaccordingtoserumlevels.

Methodofadministration

ClopixolAcuphaseisadministeredbyintramuscularinjectionintotheupperouterquadrantoftheglutealregion.Injection

volumesexceeding2mlshouldbedistributedbetweentwoinjectionsites.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1)

Circulatorycollapse

Depressedlevelofconsciousnessduetoanycause(e.g.intoxicationwithalcohol,barbituratesoropiates)

Coma

Useinchildren

Useinsenileconfusionalstates

4.4Specialwarningsandprecautionsforuse

Extrapyramidalreactionsintheformofacutedystonias(includingoculogyriccrisis),parkinsonianrigidity,tremor,

akinesiaandakathisiahavebeenreportedandmayoccurevenatlowerdosageinsusceptiblepatients.Sucheffects

wouldusuallybeencounteredearlyintreatment,butdelayedreactionsmayalsooccur.Antiparkinsonagentsshould

notbeprescribedroutinelybecauseofthepossibleriskofprecipitatingtoxic-confusionalstates,impairingefficacyor

causinganticholinergicside-effects.Theyshouldonlybegivenifrequiredandtheirrequirementreassessedatregular

intervals.

Tardivedyskinesiacanoccurwithneuroleptictreatment.Itismorecommonathighdosesforprolongedperiodsbut

hasbeenreportedatlowerdosageforshortperiods.Theriskseemstobegreaterintheelderly,especiallyfemales.It

hasbeenreportedthatfinevermicularmovementsofthetongueareanearlysign.Ithasbeenobservedoccasionallyin

patientsreceivingzuclopenthixol.Theconcurrentuseofanticholinergicantiparkinsondrugsmayexacerbatethiseffect.

Thepotentialirreversibilityandseriousness,aswellastheunpredictabilityofthesyndrome,requiresespeciallycareful

assessmentoftheriskversusbenefit,andthelowestpossibledosageanddurationoftreatmentconsistentwith

therapeuticefficacy.Short-liveddyskinesiamayoccurafterabruptwithdrawalofthedrug.

Thehormonaleffectsofantipsychoticneurolepticdrugsincludehyperprolactinaemia,whichmaybeassociatedwith

galactorrhoea,gynaecomastia,oligomenorrhoeaoramenorrhoea.Sexualfunction,includingerectionandejaculation

maybeimpaired;butincreasedlibidohasalsobeenreported.

Thepossibilityofdevelopmentofneurolepticmalignantsyndromeexistswithanyneuroleptic.Theriskispossibly

greaterwiththemorepotentagents.Patientswithpre-existingorganicbrainsyndrome,mentalretardationandopiate

andalcoholabuseareover-representedamongfatalcases.RarecasesreportedasNMShavealsobeenreceivedin

associationwithzuclopenthixol.ClinicalmanifestationsofNMSarehyperpyrexia,musclerigidity,alteredmental

status,andevidenceofautonomicinstability(irregularpulseorbloodpressure,tachycardia,sweatingandcardiac

arrhythmia).Additionalsignsmayincludeelevatedcreatinine,phosphokinase,myoglubinuria( rhabdomyolysis ),and

acuterenalfailure.IfapatientdevelopssignsandsymptomsindicativeofNMSorpresentswithunexplainedhigh

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discontinued.Symptomsmaypersistformorethanaweekafteroralneurolepticsarediscontinuedandsomewhat

longerwhenassociatedwiththedepotformsofthedrugs.

Likeotherantipsychoticszuclopenthixolacetateshouldbeusedwithcautioninpatientswithorganicbrainsyndrome,

convulsionandadvancedhepaticdisease.

Zuclopenthixolshouldalsobeusedwithcautioninpatientswhoareexcitableoroveractive,inpatientswithconvulsive

disorders,severeatherosclerosis,severerespiratorydiseaseandParkinson’sdisease.Careshouldalsobetakenin

patientswithpersonalorfamilyhistoryofnarrowangleglaucoma.

AdministrationtopatientswithParkinsonismorextrapyramidaldiseasemayinduceanexacerbationofthatdisorder.

Asdescribedforotherpsychotropicszuclopenthixolacetatemaymodifyinsulinandglucoseresponsescallingfor

adjustmentoftheantidiabetictherapyindiabeticpatients.

Thegeneralcautionforuseofneurolepticsinhypothyroidism,thyrotoxicosis,myastheniagravisorprostatic

hypertrophyshouldbeobserved,butthereisnoevidencetosuggestthatzuclopenthixolgivesrisetoanyparticular

probleminsuchconditions.

Patientsonlong-termtherapy,particularlyonhighdoses,shouldbemonitoredcarefullyandevaluatedperiodicallyto

decidewhetherthemaintenancedosagecanbelowered.

Aswithotherdrugsbelongingtothetherapeuticclassofantipsychotics,zuclopenthixolacetatemaycauseQT

prolongation.PersistentlyprolongedQTintervalsmayincreasetheriskofmalignantarrhythmias.Therefore,

zuclopenthixolacetateshouldbeusedwithcautioninsusceptibleindividuals(withhypokalemia,hypomagnesaemiaor

familyhistoryofQTprolongation)andinpatientswithahistoryofcardiovasculardisorders,e.g.QTprolongation,

significantbradycardia(<50beatsperminute),arecentacutemyocardialinfarction,uncompensatedheartfailure,or

cardiacarrhythmia.Concomitanttreatmentwithotherantipsychoticsshouldbeavoided(seesection4.5).

Casesofvenousthromboembolism(VTE)havebeenreportedwithantipsychoticdrugs.Sincepatientstreatedwith

antipsychoticsoftenpresentwithacquiredriskfactorsforVTE,allpossibleriskfactorsforVTEshouldbeidentified

beforeandduringtreatmentwithClopixolandpreventivemeasuresundertaken.

Elderly

Careshouldalsobetakenintheelderly,particularlyiffrailoratriskofhypothermia,sedation,hypotensionorconfusion.

Cerebrovascular

Anapproximately3-foldincreasedriskofcerebrovascularadverseeventshavebeenseeninrandomisedplacebo

controlledclinicaltrialsinthedementiapopulationwithsomeatypicalantipsychotics.Themechanismforthis

increasedriskisnotknown.Anincreasedriskcannotbeexcludedforotherantipsychoticsorotherpatientpopulations.

Zuclopenthixolacetateshouldbeusedwithcautioninpatientswithriskfactorsforstroke.

IncreasedMortalityinElderlypeoplewithDementia

Datafromtwolargeobservationalstudiesshowedthatelderlypeoplewithdementiawhoaretreatedwith

antipsychoticsareatasmallincreasedriskofdeathcomparedwiththosewhoarenottreated.Thereareinsufficient

datatogiveafirmestimateoftheprecisemagnitudeoftheriskandthecauseoftheincreasedriskisnotknown.

Clopixolisnotlicensedforthetreatmentofdementia-relatedbehaviouraldisturbances.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsrequiringprecautionsforuse

Zuclopenthixolmayenhancethesedativeeffectofalcohol,andtheeffectsofbarbituratesandotherCNSdepressants

andmaypotentiatetheeffectsofgeneralanaesthetics.

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Concomitantuseofmetoclopramideandpiperazineincreasestheriskofextrapyramidaldisorder.

Neurolepticsmayincreaseorreducetheeffectofantihypertensivedrugs,theantihypertensiveeffectofguanethidine

andsimilaractingcompoundsisreduced.

Concomitantuseofneurolepticsandlithiumincreasestheriskofneurotoxicity.

Tricyclicantidepressantsandneurolepticsmutuallyinhibitthemetabolismofeachother.

Neurolepticsmayenhancetheabsorptionofcorticosteroidsanddigoxin,thehypotensiveeffectsofvasodilator

antihypertensiveagentssuchashydralazineandprolongtheactionofneuromuscularblockingagents.

SincezuclopenthixolispartlymetabolisedbyCYP2D6,concomitantuseofdrugsknowntoinhibitthisenzymemay

leadtodecreasedclearanceofzuclopenthixol.

Asforotheratypicalantipsychotics,cautionisadvisedinpatientstakingzuclopenthixolinconcomitantusewithoral

anticoagulants(e.g.warfarin),andothermedicinalproductsknowntoaffectplateletfunction(e.g.phenothiazines,most

tricyclicantidepressants,acetylsalicyclicacid,andnon-steroidalanti-inflammatorymedicinalproducts(NSAIDs),

ticlopidineanddipyridamole).

IncreasesintheQTintervalrelatedtoantipsychotictreatmentmaybeexacerbatedbytheco -administrationofother

drugsknowntosignificantlyincreasetheQTinterval.Co-administrationofsuchdrugsshouldbeavoided.Relevant

classesinclude:

classIaandIIIantiarrhythmics(e.g.quinidine,amiodarone,sotalol,dofetilide)

someantipsychotics(e.g.thioridazine)

somemacrolides(e.g.erythromycin)

someantihistamines(e.g.terfenadine,astemizole)

somequinoloneantibiotics(e.g.gatifloxacin,moxifloxacin)

TheabovelistisnotexhaustiveandotherindividualdrugsknowntosignificantlyincreaseQTinterval(e.g.cisapride,

lithium)shouldbeavoided.

Drugsknowntocauseelectrolytedisturbancessuchasthiazidediuretics(hypokalaemia)anddrugsknowntoincrease

theplasmaconcentrationofzuclopenthixolacetateshouldalsobeusedwithcautionastheymayincreasetheriskofQT

prolongationandmalignantarrhythmias(seesection4.4).

4.6Fertility,pregnancyandlactation

Pregnancy

Patientsshouldbeadvisedtonotifytheirphysicianiftheybecomepregnantorintendtobecomepregnantduring

treatmentwithzuclopenthixol.

Duetoinsufficientsafetyinformationinhumansandconcernsraisedbyanimalreproductivestudies,thismedicinal

productshouldnotbeusedinpregnancyunlesstheexpectedbenefitclearlyjustifiesthepotentialrisktothefoetus.

Thenewbornsofmotherstreatedwithneurolepticsinlatepregnancy,orlabour,mayshowsignsofintoxicationsuchas

lethargy,tremorandhyperexcitabilityandhavealowapgarscore.

Animalembryo-foetaldevelopmentalreproductionstudiesonzuclopenthixolhavenotgivenevidenceofanincreased

incidenceoffoetalmalformationsoreffectsonembryoviability.Ananimalpreandpostnatalstudyshowedan

increaseinstillbirths,reducedpupsurvivalanddelayeddevelopmentofpupsatdoselevelscausingmaternaltoxicity.

Thepotentialriskforhumansisunknown.

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adversereactionsincludingextrapyramidaland/orwithdrawalsymptomsthatmayvaryinseverityandduration

followingdelivery.Therehavebeenreportsofagitation,hypertonia,hypotonia,tremor,somnolence,respiratory

distress,orfeedingdisorder.Consequently,newbornsshouldbemonitoredcarefully.

Lactation

Aszuclopenthixolisfoundinbreastmilkinlowconcentrations,breast-feedingshouldnotbecontinuedduringtherapy

unlessintheopinionofthephysiciantheexpectedbenefittothepatientoutweighsthepotentialrisktotheinfant.

4.7Effectsonabilitytodriveandusemachines

ClopixolAcuphaseisasedativedrug.Patientswhoareprescribedpsychotropicmedicationmaybeexpectedtohavesome

impairmentingeneralattentionandconcentrationandshouldbecautionedabouttheirabilitytodriveoroperate

machinery.

4.8Undesirableeffects

Undesirableeffectsareforthemajoritydosedependent.Thefrequencyandseverityaremostpronouncedintheearly

phaseoftreatmentanddeclineduringcontinuedtreatment.

Extrapyramidalreactionsmayoccur,especiallyduringthefirstfewdaysafteraninjectionandintheearlyphaseof

treatment.Inmostcasesthesesideeffectscanbesatisfactorilycontrolledbyreductionofdosageand/oruseof

antiparkinsoniandrugs.Theroutineprophylacticuseofantiparkinsoniandrugsisnotrecommended.Antiparkinsonian

drugsdonotalleviatetardivedyskinesiaandmayaggravatethem.Reductionindosageor,ifpossible,discontinuation

ofzuclopenthixoltherapyisrecommended.Inpersistentakathisiaabenzodiazepineorpropranololmaybeuseful.

Frequenciesaretakenfromtheliteratureandspontaneousreporting.Frequenciesaredefinedas:

verycommon(1/10),common(1/100to<1/10),uncommon(1/1000to<1/100),rare(1/10000to<1/1000),veryrare

(<1/10000),ornotknown(cannotbeestimatedfromtheavailabledata).

Cardiacdisorders Common Tachycardia,palpitations.

Rare ElectrocardiogramQTprolonged.

Bloodandlymphatic

systemdisorders Rare Thrombocytopenia,neutropenia,

leukopenia,agranulocytosis.

Nervoussystemdisorders Verycommon Somnolence,akathisia,hyperkinesia,

hypokinesia.

Common Tremor,dystonia,hypertonia,dizziness,

headache,paraesthesia,disturbancein

attention,amnesia,gaitabnormal.

Uncommonto

Rare Tardivedyskinesia,hyperreflexia,

dyskinesia,parkinsonism,syncope,ataxia,

speechdisorder,hypotonia,convulsion,

migraine.

Veryrare Neurolepticmalignantsyndrome.

Eyedisorders Common Accommodationdisorder,visionabnormal.

Uncommon Oculogyration,mydriasis.

Earandlabyrinth

disorders Common Vertigo.

Uncommon Hyperacusis,tinnitus.

Respiratory,thoracicand

mediastinaldisorders Common Nasalcongestion,dyspnoea.

Gastrointestinaldisorders Verycommon Drymouth.

Common Salivaryhypersecretion,constipation,

vomiting,dyspepsia,diarrhoea.

Uncommon Abdominalpain,nausea,flatulence.

Renalandurinary

disorders Common Micturitiondisorder,urinaryretention,

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Localisederythema,pruritusandinjectionsitenodulearethemosttypicalinjectionsitereactions.

Aswithotherdrugsbelongingtothetherapeuticclassofantipsychotics,rarecasesofQTprolongation,ventricular

arrhythmias-ventricularfibrillation,ventriculartachycardia,TorsadedePointesandsuddenunexplaineddeathhave

beenreportedforzuclopenthixolacetate(seesection4.4).

Abruptdiscontinuationofzuclopenthixolacetatemaybeaccompaniedbywithdrawalsymptoms.Themostcommon

symptomsarenausea,vomiting,anorexia,diarrhoea,rhinorrhoea,sweating,myalgias,paraesthesias,insomnia,

restlessness,anxiety,andagitation.Patientsmayalsoexperiencevertigo,alternatefeelingsofwarmthandcoldness,

andtremor.Symptomsgenerallybeginwithin1to4daysofwithdrawalandabatewithin7to14days.

4.9Overdose

Duetotheadministrationformoverdosesymptomsareunlikelytooccur.

Symptoms

Somnolence,coma,movementdisorders,convulsions,shock,hyperthermia/hypothermia.

ECGchanges,QTprolongation,TorsadedePointes,cardiacarrestandventriculararrthymiashavebeenreportedwhen

Skinandsubcutaneous

tissuedisorders Common Hyperhidrosis,pruritus.

Uncommon Rash,photosensitivityreaction,

pigmentationdisorder,seborrhoea,

dermatitis,purpura.

Musculoskeletaland

connectivetissuedisorder Common Myalgia.

Uncommon Musclerigidity,trismus,torticollis.

Endocrinedisorders Rare Hyperprolactinaemia.

Metabolismandnutrition

disorders Common Increasedappetite,weightincreased.

Uncommon Decreasedappetite,weightdecreased.

Rare Hyperglycaemia,glucosetolerance

impaired,hyperlipidaemia.

Vasculardisorders Uncommon Hypotension,hotflush.

Veryrare Venousthromboembolism

Generaldisordersand

administrationsite

conditions Common Asthenia,fatigue,malaise,pain.

Uncommon Thirst,injectionsitereaction,hypothermia,

pyrexia.

Immunesystemdisorders Rare Hypersensitivity,anaphylacticreaction.

Hepato-biliarydisorders Uncommon Liverfunctiontestabnormal.

Veryrare Cholestatichepatitis,jaundice.

Pregnancy,puerperium

andperinatalconditions. Notknown Drugwithdrawalsyndrome

neonatal(see4.6)

Reproductivesystemand

breastdisorders Uncommon Ejaculationfailure,erectiledysfunction,

femaleorgasmicdisorder,vulvovaginal

dryness.

Rare Gynaecomastia,galactorrhoea,

amenorrhoea,priapism.

Psychiatricdisorders Common Insomnia,depression,anxiety,nervousness,

abnormaldreams,agitation,libido

decreased.

Uncommon Apathy,nightmare,libidoincreased,

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Treatment

Treatmentissymptomaticandsupportive.Measurestosupporttherespiratoryandcardiovascularsystemsshouldbe

instituted.Adrenaline(epinephrine)shouldnotbeusedasfurtherloweringofbloodpressuremayresult.Convulsions

maybetreatedwithdiazepamandmovementdisorderswithbiperiden.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup

Neuroleptics(antipsychotics)

ATC-code:N05AF05

Mechanismofaction

Zuclopenthixolisaneurolepticofthethioxanthenegroup.

Theantipsychoticeffectofneurolepticsisrelatedtotheirdopaminereceptorblockingeffectbutpossiblyalso5 -HT(5-

hydroxytryptamine)receptorblockadecontributes.InvitrozuclopenthixolhashighaffinityforbothdopamineD

andD

receptors,for

-adrenoceptorsand5 -HT

receptorsbutnoaffinityforcholinergicmuscarinereceptors.Ithasweak

histamine(H

)receptoraffinityandno

-adrenoceptorblockingactivity.

InvivotheaffinityforD

bindingsitesdominatesovertheaffinityforD

receptors.Zuclopenthixolhasproventobea

potentneurolepticinallthebehaviouralstudiesforneuroleptic(dopaminereceptorblocking)activity.Correlationisfound

intheinvivotestmodels,theaffinityfordopamineD

bindingsitesinvitroandtheaverage,dailyoralantipsychoticdoses.

Likemostotherneurolepticszuclopenthixolincreasestheserumprolactinlevel.

Pharmacologicalstudiesshowedapronouncedeffect4hoursafterparenteralapplicationofzuclopenthixolacetateinoil.

Somewhatmoremarkedeffectwasrecordedintheperiodonetothreedaysaftertheinjection.Duringthefollowingdays

theeffectdeclinedrapidly.

Clinicalefficacy

Inclinicalusezuclopenthixolacetateisintendedfortheinitialtreatmentofacutepsychoses,maniaandexacerbationof

chronicpsychoses.

Asingleinjectionofzuclopenthixolacetateensuresapronouncedandrapidreductionofpsychoticsymptoms.Theduration

ofactionistwotothreedaysandnormallyonlyoneortwoinjectionsaresufficientbeforethepatientscanbeswitchedto

oralordepottreatment.

Besidescausingasignificantreductionorcompleteeliminationofthenuclearsymptomsofschizophreniasuchas

hallucinations,delusionsandthoughtdisturbanceszuclopenthixolalsohasamarkedeffectonaccompanyingsymptoms

likehostility,suspiciousness,agitationandaggressiveness.

Zuclopenthixolinducesatransientdose-dependentsedation.However,suchaninitialsedationisusuallyadvantageousin

theacutephaseofthepsychosisasitcalmsthepatientintheperiodbeforetheantipsychoticeffectsetsin.Theunspecific

sedationispresentrapidlyaftertheinjection,issignificantafter2hoursandreachesitsmaximuminabout8hours,

whereuponitdeclinessubstantiallyandremainsweakinspiteofrepeatedinjection.

Zuclopenthixolacetateisparticularlyusefulinthetreatmentofpsychoticpatients,whoareagitated,restless,hostile,or

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5.2Pharmacokineticproperties

Absorption

Byesterificationofzuclopenthixolwithaceticacidzuclopenthixolhasbeenconvertedtoamorelipophilicsubstance,

zuclopenthixolacetate.Whendissolvedinoilandinjectedintramuscularlytheesterdiffusesratherslowlyfromtheoilto

thebodywaterphasewhereitisrapidlyhydrolysedreleasingtheactivezuclopenthixol.

Followingintramuscularinjectionmaximumserumconcentrationisreachedoveraperiodof24-48hours(average36

hours).Themeanplasmaeliminationhalf-life(reflectingthereleasefromthedepot)isabout32hours.

Distribution

Theapparentvolumeofdistribution(V

)isabout20l/kg.

Theplasmaproteinbindingisabout98-99%.

Biotransformation

Themetabolismofzuclopenthixolproceedsalongthreemainroutes-sulphoxidation,sidechainN-dealkylationand

glucuronicacidconjugation.Themetabolitesaredevoidofpsychopharmacologicalactivity.Zuclopenthixoldominates

overmetabolitesinbrainandothertissues.

Elimination

Theeliminationhalf-life(T

)ofzuclopenthixolisabout20hoursandthemeansystemicclearance(Cl

)isabout0.86

l/min.

Zuclopenthixolisexcretedmainlywithfaeces,butalsotosomedegree(about10%)withtheurine.Onlyabout0.1%of

thedoseisexcretedunchangedwiththeurine,meaningthatthedrugloadonthekidneysisnegligible.

Innursingmotherszuclopenthixolisexcretedinsmallamountswiththebreastmilk.Insteadystatethepre-dosemeanratio

milkconc./serumconc.inwomentreatedorallyorwiththedecanoatewasabout0.29.

Linearity

Thekineticsislinear.Averagemaximumserumlevelofzuclopenthixolcorrespondingtoa100mgdoseofzuclopenthixol

acetateis102nmol/l(41ng/ml).Threedaysaftertheinjectiontheserumlevelisaboutonethirdofthemaximumi.e.35

nmol/l(14ng/ml).

Elderlypatients

Thepharmacokineticparametersareindependentoftheageofthepatients.

Reducedrenalfunction

Basedontheabovecharacteristicsforeliminationitisreasonabletoassumethatreducedkidneyfunctionislikelynotto

havemuchinfluenceontheserumlevelsofparentdrug.

Reducedhepaticfunction

Nodataavailable.

Polymorphism

Aninvivoinvestigationhasshownthatsomepartofthemetabolicpathwaysissubjecttogeneticpolymorphismofthe

sparteine/debrisoquineoxidation(CYP2D6).

5.3Preclinicalsafetydata

Acutetoxicity

Zuclopenthixolhaslowacutetoxicity.

Chronictoxicity

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Reproductiontoxicity

Zuclopenthixolwastestedfordevelopmentaltoxicityinratsandrabbitsafteroraladministration.Undertheconditionsof

thestudies,zuclopenthixoldidnotinducemalformationsoraffectembryo-foetalviability.

However,inaperi/postnatalstudyinrats,dosagesof5and15mg/kg/dayresultedinanincreaseofstillbirths,reducedpup

survivalanddelayeddevelopmentofpups.Theclinicalsignificanceofthesefindingsisunclearanditispossiblethatthe

effectonpupswasduetoneglectfromthedamsthatwereexposedtodosesofzuclopenthixolproducingmaternaltoxicity.

Mutagenicityandcarcinogenicity

Zuclopenthixolhasnomutagenicorcarcinogenicpotential.Inaratoncogenecitystudy30mg/kg/dayfortwoyears(top

dosage)resultedinslightnon-statisticalincreasesintheincidenceofmammaryadenocarcinomas,pancreaticisletcell

adenomas,carcinomasinfemales,andthyroidparafollicularcarcinomas.Theslightincreaseintheincidenceofthese

tumorsisacommonfindingforD

antagonists,whichincreaseprolactinsecretionwhenadministeredtorats.The

physiologicaldifferencesbetweenratsandhumanswithregardtoprolactinmaketheclinicalsignificanceofthesefindings

unclear,butitisacceptedasnotpredictinganoncogenicriskinpatients.

Localtoxicity

Localmuscledamageisseenafterinjectionofaqueoussolutionsofneuroleptics,includingzuclopenthixol.Themuscle

damageshowsamuchhigherdegreeaftertheaqueoussolutionsofneurolepticsthanaftertheoilysolutionsof

zuclopenthixolacetateandzuclopenthixoldecanoate.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Triglycerides,mediumchain

6.2Incompatibilities

Intheabsenceofcompatabilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproductsapartfrom

otherinjectionsintheClopixolrange(seesection4.2).

6.3Shelflife

2yearsaspackagedforsale.

Onceopeneduseimmediatelyanddiscardanyunusedsolution.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keeptheampoulesintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Aclearglass(TypeIPh.Eur.)ampoulecontainingzuclopenthixolacetate50mgin1mlofthinvegetableoil.

Theampoulesarepackedinboxesof5.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

LundbeckLtd.

LundbeckHouse

CaldecotteLakeBusinessPark

Caldecotte

MiltonKeynesMK78LG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA115/5/9

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation: 18October1990

Dateoflastrenewal: 18October2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 29/03/2012 CRN 2110129 page number: 10