GEODON

Main information

  • Trade name:
  • GEODON Oral Suspension 10
  • Dosage:
  • 10
  • Pharmaceutical form:
  • Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GEODON Oral Suspension 10
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0019/052/006
  • Authorization date:
  • 29-10-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GEODON10mg/mloralsuspension.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontainsziprasidonehydrochloridemonohydrateequivalentto10mgofziprasidone.

Excipients:

Eachmlcontains1.36mgmethylparahydroxybenzoate.

Eachmlcontains0.17mgpropylparahydroxybenzoate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Oralsuspension

Whitetoslightlyyellowopaquecherryflavouredaqueoussuspension.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ziprasidoneisindicatedforthetreatmentofschizophreniainadults.

Ziprasidoneisindicatedforthetreatmentofmanicormixedepisodesofmoderateseverityinbipolardisorderinadults,

childrenandadolescentsaged10-17years(preventionofepisodesofbipolardisorderhasnotbeenestablished-see

section5.1).

4.2Posologyandmethodofadministration

Adults

Therecommendeddose,inacutetreatmentofschizophreniaandbipolarmania,is40mgtwicedailytakenwithfood.

Dailydosagemaysubsequentlybeadjustedonthebasisofindividualclinicalstatusuptoamaximumof80mgtwice

daily.Ifindicated,themaximumrecommendeddosemaybereachedasearlyasday3oftreatment.

Itisofparticularimportancenottoexceedthemaximumdoseasthesafetyprofileabove160mg/dayhasnotbeen

confirmedandziprasidoneisassociatedwithdose-relatedprolongationoftheQTinterval(seesections4.3and4.4).

Inmaintenancetreatmentofschizophreniapatients,ziprasidoneshouldbeadministeredatthelowesteffectivedose;in

manycases,adoseof20mgtwicedailymaybesufficient.

Measurethedoseascloselyaspossibleusingtheoralsyringeprovided.Ziprasidoneoralsuspensionshouldbe

administereddirectlyintothemouth.Althoughthesuspensionshouldbetakenwithfood,itshouldnotbedilutedor

mixedintoanyfoodorbeveragespriortoadministration.

Elderly

Alowerstartingdoseisnotroutinelyindicatedbutshouldbeconsideredforthose65andoverwhenclinicalfactors

warrant.

Useinrenalimpairment

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Useinhepaticimpairment

Inpatientswithhepaticinsufficiency,lowerdosesshouldbeconsidered.(Seesections4.4and5.2).

ChildrenandAdolescents

BipolarMania:

Therecommendeddose,inacutetreatmentofbipolarmania,inpaediatricpatients(age10to17years)isasingledose

of20mgonday1,withfood.Ziprasidoneshouldsubsequentlybeadministeredwithfoodintwodailydivideddoses,

andshouldbetitratedover1-2weekstoatargetrangeof120-160mg/dayforpatientsweighing45kg,ortoatarget

rangeof60-80mg/dayforpatientsweighing<45kg.Subsequentdosingshouldbeadjustedonthebasisofindividual

clinicalstatuswithintherangeof80-160mg/dayforpatientsweighing45kg,or40-80mg/dayforpatientsweighing

<45kg.Asymmetricdosing,withmorningdoses20mgor40mglessthaneveningdoses,waspermittedintheclinical

trial.(SeeSections4.4,5.1and5.2).

Itisofparticularimportancenottoexceedtheweight-basedmaximumdoseasthesafety

profileabovethemaximumdose(160mg/dayforchildren ≥45kgand80mg/dayfor

children<45kghasnotbeenconfirmedandziprasidoneisassociatedwithdose-related

prolongationoftheQTinterval(seesections4.3and4.4)

Schizophrenia:

Thesafetyandefficacyofziprasidoneinpaediatricpatientswithschizophreniahavenotbeenestablished(seesections

4.4).

4.3Contraindications

Knownhypersensitivitytoziprasidoneoranyoftheexcipients.KnownQT-intervalprolongation.CongenitallongQT

syndrome.Recentacutemyocardialinfarction.Uncompensatedheartfailure.ArrhythmiastreatedwithclassIAandIII

antiarrhythmicmedicinalproducts.

ConcomitanttreatmentwithmedicinalproductsthatprolongtheQTinterval,suchasClassIAandIIIantiarrhythmics,

arsenictrioxide,halofantrine,levomethadylacetate,mesoridazine,thioridazine,pimozide,sparfloxacin,gatifloxacin,

moxifloxacin,dolasetronmesilate,mefloquine,sertindoleorcisapride.(Seesections4.4and4.5).

4.4Specialwarningsandprecautionsforuse

Amedicalhistory,includingassessmentoffamilyhistory,andphysicalexaminationshouldbeundertakentoidentify

patientsforwhomziprasidonetreatmentisnotrecommended(seesection4.3).

QTinterval

Ziprasidonecausesamildtomoderatedose-relatedprolongationoftheQT-interval(seesection4.8and5.1).

ZiprasidoneshouldnotbegiventogetherwithmedicinalproductsthatareknowntoprolongtheQT-interval(see

sections4.3and4.5).Cautionisadvisedinpatientswithsignificantbradycardia.Electrolytedisturbancessuchas

hypokalaemiaandhypomagnesaemiaincreasetheriskformalignantarrhythmiasandshouldbecorrectedbefore

treatmentwithziprasidoneisstarted.Ifpatientswithstablecardiacdiseasearetreated,anECGreviewshouldbe

consideredbeforetreatmentisstarted.

Ifcardiacsymptoms,suchaspalpitations,vertigo,syncopeorseizuresoccur,thenthepossibilityofamalignantcardiac

arrhythmiashouldbeconsideredandacardiacevaluationincludinganECGshouldbeperformed.IftheQTcinterval

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Therehavebeenrarepost-marketingreportsoftorsadedepointesinpatientswithmultipleconfoundingriskfactors

takingziprasidone.

ChildrenandAdolescents

Safetyandefficacyofziprasidoneinthetreatmentofschizophreniainchildrenandadolescentshasnotbeenevaluated.

Neurolepticmalignantsyndrome(NMS)

NMSisararebutpotentiallyfatalcomplexthathasbeenreportedinassociationwithantipsychoticmedicinalproducts,

includingziprasidone.ThemanagementofNMSshouldincludeimmediatediscontinuationofallantipsychotic

medicinalproducts.

Tardivedyskinesia

Thereisapotentialforziprasidonetocausetardivedyskinesiaandothertardiveextrapyramidalsyndromesafterlong-

termtreatment.Patientswithbipolardisorderareknowntobeparticularlyvulnerabletothiscategoryofsymptoms.

Thisismorefrequentwithincreaseddurationoftreatmentandincreasingage. Ifsignsandsymptomsoftardive

dyskinesiaappear,dosereductionordiscontinuationofziprasidoneshouldbeconsidered.

Seizures

Cautionisrecommendedwhentreatingpatientswithahistoryofseizures.

HepaticImpairment

Thereisalackofexperienceinpatientswithseverehepaticinsufficiencyandziprasidoneshouldbeusedwithcaution

inthisgroup(seesections4.2and5.2).

Increasedriskofcerebrovascularaccidentsinthedementiapopulation

Anapproximately3-foldincreasedriskofcerebrovascularadverseeventshasbeenseeninrandomisedplacebo-

controlledclinicaltrialsinthedementiapopulationwithsomeatypicalantipsychotics.Themechanismforthis

increasedriskisnotknown.Anincreasedriskcannotbeexcludedforotherantipsychoticsorotherpatientpopulations.

Geodonshouldbeusedwithcautioninpatientswithriskfactorsforstroke.

Geodon10mg/mloralsuspensioncontainsmethylparahydroxybenzoateandpropylparahydroxybenzoatewhichmay

causeallergicreactions(possiblydelayed).

Geodon10mg/mloralsuspensioncontains4.65mgsodiumpermldosedandthisshouldbetakenintoaccountin

patientsonacontrolledsodiumdiet.Theusualdoseisbetween4and8mltwiceadaysothetotaldailysodiumloadis

between37.2and74.4mg.

IncreasedMortalityinElderlyPatientswithDementia-RelatedPsychosis

Elderlypatientswithdementia-relatedpsychosishavebeenshowntobeatanincreasedriskofdeathcomparedwith

placebowhentreatedwithsomeantipsychoticdrugs.Studydatawithziprasidoneinthetreatmentofelderlypatients

withdementiaareinsufficienttoconcludewhetherornotthereisanincreasedriskofdeathwithziprasidoneversus

placebointhispatientpopulation.Ziprasidoneisnotapprovedforthetreatmentofelderlypatientswithdementia-

relatedpsychosis.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

PharmacokineticandpharmacodynamicstudiesbetweenziprasidoneandothermedicinalproductsthatprolongtheQT

intervalhavenotbeenperformed.Anadditiveeffectofziprasidoneandthesemedicinalproductscannotbeexcluded,

thereforeziprasidoneshouldnotbegivenwithmedicinalproductsthatprolongtheQTinterval,suchasClassIAand

IIIantiarrhythmics,arsenictrioxide,halofantrine,levomethadylacetate,mesoridazine,thioridazine,pimozide,

sparfloxacin,gatifloxacin,moxifloxacin,dolasetronmesilate,mefloquine,sertindoleorcisapride.(Seesection4.3)

Nostudiesontheinteractionofziprasidonewithothermedicinalproductshavebeenperformedinchildren

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Giventheprimaryeffectsofziprasidone,cautionshouldbeusedwhenitistakenincombinationwithothercentrally

actingmedicinalproductsandalcohol.

Effectofziprasidoneonothermedicinalproducts

AninvivostudywithdextromethorphanshowednomarkedinhibitionofCYP2D6atplasmaconcentrations50%lower

thanthoseobtainedafter40mgziprasidonetwicedaily.Invitrodataindicatedthatziprasidonemaybeamodest

inhibitorofCYP2D6andCYP3A4.However,itisunlikelythatziprasidonewillaffectthepharmacokineticsof

medicinalproductsmetabolisedbythesecytochromeP450isoformstoaclinicallyrelevantextent.

Oralcontraceptives–Ziprasidoneadministrationresultedinnosignificantchangetothepharmacokineticsofoestrogen

(ethinyloestradiol,aCYP3A4substrate)orprogesteronecomponents.

Lithium-Co-administrationofziprasidonehadnoeffectonthepharmacokineticsoflithium.

Asziprasidoneandlithiumareassociatedwithcardiacconductionchanges,thecombinationmayposeariskfor

pharmacodynamicinteractionsincludingarrhythmias.

Therearelimiteddataonco-medicationwiththemoodstabiliserscarbamazepineandvalproate.

Effectsofothermedicinalproductsonziprasidone

TheCYP3A4inhibitorketoconazole(400mg/day)increasedtheserumconcentrationsofziprasidoneby<40%.The

serumconcentrationsofS-methyl-dihydroziprasidoneandziprasidonesulphoxide,attheexpectedTmaxof

ziprasidone,wereincreasedby55%and8%respectively.

NoadditionalQTcprolongationwasobserved.Changesinpharmacokineticsduetocoadministrationofpotent

CYP3A4inhibitorsareunlikelytobeofclinicalimportance,thereforenodosageadjustmentisrequired.

Carbamazepinetherapy,200mgb.i.dfor21days,resultedinadecreaseofapproximately35%intheexposureto

ziprasidone.

Therearenodataonco-medicationwithvalproate.

Antacid-multipledosesofaluminiumandmagnesiumcontainingantacidorcimetidinehavenoclinicallysignificant

effectonthepharmacokineticsofziprasidoneunderfedconditions.

Serotonergicmedicinalproducts

Inisolatedcases,therehavebeenreportsofserotoninsyndrometemporallyassociatedwiththetherapeuticuseof

ziprasidoneincombinationwithotherserotonergicmedicinalproductssuchasSSRIs(seesection4.8).Thefeaturesof

serotoninsyndromecanincludeconfusion,agitation,fever,sweating,ataxia,hyperreflexia,myoclonusanddiarrhoea.

4.6Fertility,pregnancyandlactation

Reproductivetoxicitystudieshaveshownundesirableeffectsonthereproductiveprocess,atdosesassociatedwith

maternaltoxicityand/orsedation.Therewasnoevidenceofteratogenicity(seesection5.3).

Useinpregnancy

Nostudieshavebeenconductedinpregnantwomen.Womenofchildbearingpotentialreceivingziprasidoneshould

thereforebeadvisedtouseanappropriatemethodofcontraception.Ashumanexperienceislimited,administrationof

ziprasidoneisnotrecommendedduringpregnancyunlesstheexpectedbenefittothemotheroutweighsthepotential

risktothefoetus.

Useinlactation

Itisnotknownwhetherziprasidoneisexcretedinbreastmilk.Patientsshouldnotbreastfeedaninfantiftheyare

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4.7Effectsonabilitytodriveandusemachines

Ziprasidonemaycausesomnolenceandmayinfluencetheabilitytodriveandusemachines.Patientslikelytodriveor

operatemachinesshouldbecautionedappropriately.

4.8Undesirableeffects

Oralziprasidonehasbeenadministeredinclinicaltrials(seesection5.1)toapproximately6500adultsubjects.The

mostcommonadversereactionsinschizophreniaclinicaltrialsweresedationandakathisia.Inbipolarmaniaclinical

trials,themostcommonadversereactionsweresedation,akathisia,extrapyramidaldisorderanddizziness.

Thetablebelowcontainsadverseeventsbasedoncombinedshortterm(4-6week),fixeddose,schizophreniastudies

andshortterm(3week),flexibledose,bipolarmaniastudies,withaprobableorpossiblerelationshiptotreatmentwith

ziprasidoneandwhichoccuratanincidencegreaterthanplacebo.

Alladversereactionsarelistedbyclassandfrequency(verycommon(>1/10),common(>1/100,<1/10),uncommon

(>1/1000,<1/100)andrare(<1/1000).

Theadversereactionslistedbelowmayalsobeassociatedwiththeunderlyingdiseaseand/orconcomitantmedications.

SystemOrgan

Class Adversedrugreactions

InfectionsandInfestations

Rare Rhinitis

Metabolismandnutritiondisorders

Uncommon Increasedappetite

Rare Hypocalcaemia

Psychiatricdisorders

Common Restlessness

Uncommon Agitation,anxiety,throattightness,nightmare

Rare Panicattack,depressivesymptom,bradyphrenia,flataffect,anorgasmia

Nervoussystemdisorders

Common Dystonia,,akathisia,extrapyramidaldisorder,parkinsonism(including

cogwheelrigidity,bradykinesia,hypokinesia),tremor,dizziness,sedation,

somnolence,headache

Uncommon Generalisedtonicclonicseizures,tardivedyskinesia,dyskinesia,,drooling,

ataxia,,dysarthria,oculogyriccrisis,disturbanceinattention,hypersomnia,

hypoaesthesia,,paraesthesia,lethargy

Rare Torticollis,paresis,akinesia,hypertonia,restlesslegssyndrome

Bloodandlymphaticsystemdisorders

Rare Lymphopenia

Cardiacdisorders

Uncommon Palpitations,tachycardia

Eyedisorders

Common Visionblurred

Uncommon Photophobia

Rare Amblyopia,visualdisturbance,eyepruritis,dryeyes

Earandlabyrinthdisorders

Uncommon Vertigo,tinnitus

Rare Earpain

Vasculardisorders

Uncommon Hypertensivecrisis,hypertension,orthostatichypotension,hypotension

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Inshort-termandlong-termziprasidoneschizophreniaandbipolarmaniaclinicaltrials,theincidenceoftonicclonic

seizuresandhypotensionwasuncommon,occurringinlessthan1%ofziprasidonetreatedpatients.

Ziprasidonecausesamildtomoderatedose-relatedprolongationoftheQTinterval(seesection5.1).Inschizophrenia

clinicaltrials,anincreaseof30to60msecwasseenin12.3%(976/7941)ofECGtracingsfromziprasidone-treated

and7.5%(73/975)ofECGtracingsfromplacebo-treatedpatients.

Aprolongationof>60msecwasseenin1.6%(128/7941)and1.2%(12/975)oftracingsfromziprasidoneandplacebo-

treatedpatients,respectively.TheincidenceofQTcintervalprolongationabove500msecwas3inatotalof3266

(0.1%)inziprasidonetreatedpatientsand1inatotalof538(0.2%)inplacebotreatedpatients.Comparablefindings

wereobservedinbipolarmaniaclinicaltrials.

Inlongtermmaintenancetreatmentinschizophreniaclinicaltrials,prolactinlevelsinpatientstreatedwithziprasidone

weresometimeselevated,but,inmostpatients,returnedtonormalrangeswithoutcessationoftreatment.Inaddition,

potentialclinicalmanifestations(e.g.gynaecomastiaandbreastenlargement)wererare.

ChildrenandAdolescentswithBipolarmania

Oralziprasidonehasbeenadministeredinclinicaltrials(seesection5.1)to208paediatricsubjectswithbipolar

disorder.Themostfrequentadversereactions(reportedwithafrequency>10%)weresedation,somnolence,headache,

fatigueandnausea.Thefrequency,typeandseverityofadversereactionsinthesesubjectsweregenerallysimilarto

thoseinadultswithbipolardisorderwhoaretreatedwithziprasidone.

Ziprasidonewasassociatedwithasimilarmildtomoderatedose-relatedprolongationoftheQTintervalinthe

paediatricbipolarclinicaltrialtothoseseenintheadultpopulation.Tonicclonicseizuresandhypotensionwerenot

Respiratory,thoracicandmediastinaldisorders

Uncommon Dyspnoea,sorethroat

Rare Hiccups

Gastrointestinaldisorders

Common Nausea,vomiting,constipation,dyspepsia,drymouth,salivary

hypersecretion

Uncommon Diarrhoea,dysphagia,gastritis,gastrointestinaldiscomfort,swollentongue,

tonguethick,flatulence

Rare Gastro-oesophagealreflux,loosestools

Skinandsubcutaneoustissuedisorders

Uncommon Urticaria,rash,rashmaculo-papular,acne

Rare Psoriasis,dermatitisallergic,alopecia,swellingface,erythema,rash

papular,skinirritation

Musculoskeletalandconnectivetissuedisorders

Common Musculoskeletalrigidity

Uncommon Musculoskeletaldiscomfort,musclecramp,paininextremity,jointstiffness

Rare Trismus

Renalandurinarydisorders

Rare Urinaryincontinence,dysuria

Reproductivesystemandbreastdisorders

Rare Erectiledysfunction,erectionincreased,galactorrhoea,gynaecomastia

Generaldisordersandadministrationsiteconditions

Common Asthenia,fatigue

Uncommon Chestdiscomfort,gaitabnormal,pain,thirst

Rare Pyrexia,feelinghot

Investigations

Uncommon hepaticenzymeincreased

Rare ElectrocardiogramQTcorrectedintervalprolonged,liverfunctiontest

abnormal,bloodlactatedehydrogenaseincreased,eosinophilcount

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PostMarketing:

Thefollowingtableofadverseeventsisbasedonreportsfrompostmarketingexperiencewithziprasidone:

4.9Overdose

Experiencewithziprasidoneinoverdoseislimited.Thelargestsingleingestionofziprasidoneis12,800mg.Inthis

caseextrapyramidalsymptomsandaQT/QTcprolongationof446msec(withnocardiacsequelae)werereported.In

general,themostcommonlyreportedsymptomsfollowingoverdoseare,extrapyramidalsymptoms,somnolence,

tremorandanxiety.

Thepossibilityofobtundation,seizuresordystonicreactionoftheheadandneckfollowingoverdosemaycreatearisk

ofaspirationwithinducedemesis.Cardiovascularmonitoringshouldcommenceimmediatelyandshouldinclude

continuouselectrocardiographicmonitoringtodetectpossiblearrhythmias.Thereisnospecificantidotetoziprasidone.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antipsychotic,indolederivatives,ATCcodeNO5AE04.

Ziprasidonehasahighaffinityfordopaminetype2(D

)receptorsandsubstantiallyhigheraffinityforserotonintype

(5HT

)receptors.Receptorblockade,12hoursafterasingledoseof40mg,wasgreaterthan80%forserotonin

type2

andgreaterthan50%forD

usingpositronemissiontomography(PET).Ziprasidonealsointeractswith

serotonin5HT

,5HT

and5HT

receptorswhereitsaffinitiesforthesesitesareequaltoorgreaterthanitsaffinity

fortheD

receptor.Ziprasidonehasmoderateaffinityforneuronalserotoninandnorepinephrinetransporters.

ZiprasidonedemonstratesmoderateaffinityforhistamineH(1)-andalpha(1)-receptors.Ziprasidonedemonstrates

negligibleaffinityformuscarinicM(1)-receptors.

Ziprasidonehasbeenshowntobeanantagonistatbothserotonintype2

(5HT

)anddopaminetype2(D

receptors.Itisproposedthatthetherapeuticactivityismediated,inpart,throughthiscombinationofantagonist

activities.Ziprasidoneisalsoapotentantagonistat5HT

and5HT

receptors,apotentagonistatthe5HT

receptorandinhibitsneuronalreuptakeofnorepinephrineandserotonin.

Furtherinformationonclinicaltrials

Schizophrenia

SystemOrganClass Adversedrugreactions

Immunesystemdisorders Anaphylacticreaction

Psychiatricdisorders Insomnia;mania/hypomania

NervousSystem

Disorders Neurolepticmalignantsyndrome;serotoninsyndrome(seesection

4.5);facialdroop

Vasculardisorders Syncope

Cardiacdisorders Torsadedepointes(seesection4.4)

Skinandsubcutaneous

tissuedisorders Hypersensitivity,angioedema

RenalandUrinary

disorders Enuresis

Reproductivesystemand

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patientswhoshowedaninitialtreatmentresponse:therewasnoclearevidenceforadose-responserelationship

amongsttheziprasidonegroups.Inthisstudy,whichincludedpatientswithbothpositiveandnegativesymptoms,

ziprasidone'sefficacywasdemonstratedinbothpositiveandnegativesymptoms.

Theincidenceofbodyweightgain,reportedasanadverseeventinshortterm(4-6week)schizophreniastudieswas

lowandidenticalinziprasidone-treatedandplacebo-treatedpatients(both0.4%).Inaone-yearplacebo-controlled

studyamedianweightlossof1-3kgwasobservedinziprasidone-treatedpatientscomparedtoa3kgmedianlossin

placebo-treatedpatients.

Inadouble-blindcomparativeschizophreniastudy,metabolicparametersincludingweightandfastinglevelsofinsulin,

totalcholesterolandtriglyceridesandaninsulinresistance(IR)indexweremeasured.Inpatientsreceivingziprasidone

nosignificantchangesfrombaselinewereobservedinanyofthesemetabolicparameters.

Resultsofalargepost-marketingsafetystudy

Arandomisedpost-approvalstudyof18,239schizophrenicpatientswithobservationalfollow-upfor1yearwas

conductedtodeterminewhetherziprasidone´seffectontheQTcintervalisassociatedwithanincreasedriskofnon-

suicidemortality.Thisstudy,whichwasconductedinnaturalisticclinicalpracticesettings,showednodifferenceinthe

rateofover-allnon-suicidemortalitybetweenziprasidoneandolanzapinetreatments(primaryend-point).Thestudy

alsoshowednodifferenceinsecondaryend-pointsofall-causemortality,mortalityduetosuicide,mortalitydueto

suddendeath,however,anon-significantnumericallyhigherincidenceofcardiovascularmortalitywasobservedinthe

ziprasidonegroup.Astatisticallysignificantlyhigherincidenceofall-causehospitalisation,mainlyduetodifferences

inthenumberofpsychiatrichospitalisations,wasalsoobservedintheziprasidonegroup.

Bipolarmania

Theefficacyofziprasidoneinadultswithmaniawasestablishedintwoplacebocontrolled,doubleblind,3week

studieswhichcomparedziprasidonewithplaceboandonedoubleblind,12weekstudywhichcomparedziprasidoneto

haloperidolandplacebo.Thesestudiesincludedapproximately850patientsmeetingDSM-IVcriteriaforbipolarI

disorderwithanacutemanicormixedepisode,withorwithoutpsychoticfeatures.Thebaselinepresenceofpsychotic

featuresinthestudieswas49.7%,34.7%or34.9%.EfficacywasassessedusingtheManiaRatingScale(MRS).The

ClinicalGlobalImpression-Severity(CGI-S)scalewaseitheraco-primaryorkeysecondaryefficacyvariableinthese

studies.Ziprasidonetreatment(40-80mgBID,meandailydose120mg)resultedinstatisticallysignificantlygreater

improvementinbothMRSandCGI-SscoresatLastVisit(3weeks)comparedwithplacebo.Inthe12weekstudy,

haloperidoltreatment(meandailydose16mg)producedsignificantlygreaterreductionsinMRSscorescomparedwith

ziprasidone(meandailydose121mg).Ziprasidonedemonstratedcomparableefficacytohaloperidolintermsofthe

proportionofpatientsmaintainingaresponsetotreatmentfromweek3toweek12.

TheefficacyofziprasidoneinthetreatmentofBipolarIDisorderinpaediatricpatients(10to17yearsofage)was

evaluatedinonefour-weekplacebo-controlledtrial(n=237)ofinpatientsoroutpatientswhometDSM-IVcriteriafor

BipolarIDisordermanicormixedepisodeswithorwithoutpsychoticfeaturesandhadaY-MRSscore ≥17atbaseline.

Thisdouble-blind,placebo-controlledtrialcomparedflexibly-dosedoralziprasidone(80-160mg/day(40-80mgBID)

intwodivideddosesforpatientsweighing45kg;40-80mg/day(20-40mgBID)forpatientsweighing<45kg)to

placebo.Ziprasidonewasadministeredasasingledoseof20mgonthefirstday,thentitratedover1-2weeks,intwo

dailydoses,toatargetrangeof120-160mg/dayforpatientsweighing45kg,or60-80mg/dayforpatientsweighing

<45kg.Asymmetricdosing,withmorningdoses20mgor40mglessthaneveningdoses,waspermitted.Ziprasidone

wassuperiortoplaceboinchangefrombaselinetoweek4ontheY-MRStotalscore.Inthisclinicaltrial,themean

dailydosesadministeredwere119mgand69mginthepatientsweighing45kgand<45kg,respectively.

Ziprasidonehasbeenevaluatedforsafetyin208paediatricpatients(age10to17years)whoparticipatedinmultiple-

dose,clinicaltrialsinbipolarmania;atotalof82paediatricpatientswithBipolarIDisorderweredosedwithoral

ziprasidoneforatleast180days.

Ina4-weektrialinpaediatricpatients(10-17years)withbipolarmania,therewerenodifferencesbetweenziprasidone

andplacebopatientsinthemeanchangefrombaselineinbodyweightfastingglucose,totalcholesterol,LDL

cholesterol,ortriglyceridelevels.

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childrenandadolescents.

Therearenolong-termclinicalstudiesinvestigatingtheefficacyofziprasidoneinthepreventionofrecurrenceof

manic/depressivesymptoms.

5.2Pharmacokineticproperties

Absorption:Followingoraladministrationofmultipledosesofziprasidonewithfood,peakserumconcentrations

typicallyoccur6to8hourspost-dose.Theabsolutebioavailabilityofa20mgdoseis60%inthefedstate.

Pharmacokineticstudieshavedemonstratedthatthebioavailabilityofziprasidoneisincreasedbyupto100%inthe

presenceoffood.Itisthereforerecommendedthatziprasidoneshouldbetakenwithfood.

Inamultipledosestudyziprasidoneoralsuspensionwasshowntobebioequivalenttoziprasidonecapsulesunder

steady-stateconditions.Inasingledoseadministrationstudy,equivalencewasdemonstratedwithregardtoAUC.The

meanCmaxoftheoralsuspensionwasreducedbyapproximately10-15%ascomparedwithcapsules.Forthemultiple

dosestudy,theassociated90%confidenceintervalaroundthismeanratiowas(79.6–101.0%).

Distribution:Thevolumeofdistributionisapproximately1.1L/kg.Ziprasidoneismorethan99%proteinboundin

serum.

Biotransformationandelimination:Themeanterminalhalf-lifeofziprasidoneafteroraladministrationis6.6hours.

Steadystateisreachedwithin1-3days.Meanclearanceofziprasidoneadministeredintravenouslyis5ml/min/kg.

Approximately20%ofthedoseisexcretedinurine,andapproximately66%iseliminatedinfaeces.

Ziprasidonedemonstrateslinearkineticsoverthetherapeuticdoserangeof40to80mgtwicedailyinfedsubjects.

Ziprasidoneisextensivelymetabolisedafteroraladministrationwithonlyasmallamountexcretedinurine(<1%)or

faeces(<4%)asunchangedziprasidone.Ziprasidoneisprimarilyclearedviathreeproposedmetabolicroutestoyield

fourmajorcirculatingmetabolites,benzisothiazolepiperazine(BITP)sulphoxide,BITPsulphone,ziprasidone

sulphoxideandS-methyl-dihydroziprasidone.Unchangedziprasidonerepresentsabout44%oftotaldrug-related

materialinserum.

AninvivostudysuggeststhatconversiontoS-methyldihydroziprasidoneisthemajorrouteofmetabolismfor

ziprasidone.Invitrostudiesindicatethatthismetabolitearisesviaaldehydeoxidasecatalysedreduction,with

subsequentS-methylation.

Oxidativemetabolism,principallyviaCYP3A4withpotentialcontributionofCYP1A2,isalsoinvolved.

Ziprasidone,S-methyl-dihydroziprasidone,andziprasidonesulphoxide,whentestedinvitro,sharepropertieswhich

maypredictaQTc-prolongingeffect.S-methyl-dihydroziprasidoneismainlyeliminatedinfaecesbybiliaryexcretion

withaminorcontributionbyCYP3A4catalysedmetabolism.Ziprasidonesulphoxideiseliminatedthroughrenal

excretionandbysecondarymetabolismcatalysedbyCYP3A4.

Specialpopulations

Pharmacokineticscreeningofpatientshasnotrevealedanysignificantpharmacokineticdifferencesbetweensmokers

andnon-smokers.

Noclinicallysignificantage-orgender-differencesinthepharmacokineticsofziprasidonehasbeenobserved.The

pharmacokineticsofziprasidoneinpaediatricpatients10to17yearsofageweresimilartothoseinadultsafter

correctingforthedifferencesinbodyweights.

Consistentwiththefactthatrenalclearancecontributesverylittletoitsoverallclearance,noprogressiveincreasesin

ziprasidoneexposurewerenotedwhenziprasidonewasadministeredtosubjectswithvaryingdegreesofrenalfunction.

Exposuresinsubjectswithmild(creatinineclearance30-60ml/min),moderate(creatinineclearance10-29ml/min)and

severeimpairment(requiringdialysis)were146%,87%and75%thoseofhealthysubjects(creatinineclearance

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ofthemetabolitesareincreasedinthesepatients.

Inmildtomoderateimpairmentofliverfunction(ChildPughAorB)causedbycirrhoses,theserumconcentrations

afteroraladministrationwere30%higherandtheterminalhalf-lifewasabout2hourslongerthaninnormalpatients.

Theeffectofliverimpairmentontheserumconcentrationsofthemetabolitesisunknown.

5.3Preclinicalsafetydata

Preclinicalsafetydatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,

genotoxicityandcarcinogenicpotential.Inreproductivestudiesinratandrabbit,ziprasidonehasshownnoevidenceof

teratogenicity.Undesirableeffectsonfertilityanddecreasedpupweightswereobservedatdosescausingmaternal

toxicitysuchasdecreasedbodyweightgain.Increasedperinatalmortalityanddelayedfunctionaldevelopmentof

offspringoccurredatmaternalplasmaconcentrationsextrapolatedtobesimilartothemaximalconcentrationsin

humangiventherapeuticdoses.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Water,purified

Xylitol,E967

Sodiumchloride

Silica,colloidalanhydrous

Cherryflavour

Xanthangum,E415

Methylparahydroxybenzoate,E218

Sodiumcitrate,E331

Citricacid,anhydrous,E330

Polysorbate80,E433

Propylparahydroxybenzoate,E216

6.2Incompatibilities

Geodonoralsuspensionshouldnotbedilutedormixedintoanyfoodorbeveragespriortoadministration.

6.3ShelfLife

Shelflifeofthemedicinalproductaspackagedforsale:3years

Shelflifeafterfirstopeningthebottle:2months.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

HDPEbottles(60mlor240ml)withpolypropylenechild-resistantclosuresandlowdensitypolyethyleneliners.

Polypropyleneoralsyringe(2mlor8ml)andpolyethylenepress-inbottleadaptor.The2mloralsyringeiscalibrated

in0.25ml(2.5mg)increments;the8mloralsyringeiscalibratedin1.0ml(10mgincrements).

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PfizerLimited

RamsgateRoad

Sandwich

Kent

CT139NJ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA19/52/6

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:29October2004

Dateoflastrenewal:01August2005

10DATEOFREVISIONOFTHETEXT

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