GEODON

Main information

  • Trade name:
  • GEODON Pdr+Solv for Soln for Inj 20 Base Milligrams
  • Dosage:
  • 20 Base Milligrams
  • Pharmaceutical form:
  • Pdr+Solv for Soln for Inj
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GEODON Pdr+Solv for Soln for Inj 20 Base Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0019/052/005
  • Authorization date:
  • 08-03-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GEODON20mg/mlpowderandsolventforsolutionforinjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onevialcontainsziprasidonemesilatetodeliver20mgofziprasidone.Afterreconstitution,1mlofsolutionfor

injectioncontains20mgziprasidone.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

PowderandSolventforsolutionforinjection.

Whitetooff-whitepowder

Clearcolourlesssolvent

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ziprasidonepowderandsolventforsolutionforinjectionisindicatedfortherapidcontrolofagitationinpatientswith

schizophrenia,whenoraltherapyisnotappropriate,foramaximumof3consecutivedays.

Treatmentwithziprasidonepowderandsolventforsolutionforinjectionshouldbediscontinued,andtheuseoforal

ziprasidoneshouldbeinitiated,assoonasclinicallyappropriate.

4.2Posologyandmethodofadministration

Forintramuscularuseonly.

Intravenousadministrationmustbeavoided.

Treatmentwiththeintramuscularformulationshouldonlybeusedinpatients,wheretreatmentwithanoralformulation

isconsideredtobeinappropriate.

Adults

Therecommendeddoseis10mgadministeredasrequireduptoamaximumdoseof40mgperday.Dosesof10mg

maybeadministeredevery2hours.Somepatientsmayrequireaninitialdoseof20mg,whichcanbefollowedbya

furtherdoseof10mgafter4hours.Thereafter,dosesof10mgmaybegivenevery2hoursuptothemaximumdaily

doseof40mg.Intramuscularadministrationofziprasidoneformorethan3consecutivedayshasnotbeenstudied.

Iflong-termtherapyisindicated,oralziprasidonehydrochloridecapsules,upto80mgtwicedaily,shouldreplacethe

intramuscularadministrationassoonaspossible.

Elderly

Theclinicalexperiencewithintramusculartreatmentinelderlypatients(>65years)islimited.Treatmentwith

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Useinrenalimpairment

Ziprasidoneintramuscularinjectionshouldbeadministeredwithcautioninpatientswithimpairedrenalfunction(see

section5.2).

Useinhepaticimpairment

Inpatientswithhepaticinsufficiency,lowerdosesshouldbeconsidered.(seesection4.4and5.2).

Forinstructionsforreconstitution,seesection6.6.

4.3Contraindications

Knownhypersensitivitytoziprasidoneoranyoftheexcipients.

KnownQTintervalprolongation.CongenitallongQTsyndrome.Recentacutemyocardialinfarction.Uncompensated

heartfailure.ArrhythmiastreatedwithClassIAandIIIantiarrhythmicmedicinalproducts.

ConcomitanttreatmentwithmedicinalproductsthatprolongtheQTintervalsuchasClassIAandIIIantiarrhythmics,

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

moxifloxacin,dolasetronmesilate,mefloquine,sertindoleorcisapride.(seesection4.4andsection4.5).

4.4Specialwarningsandprecautionsforuse

QTinterval

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

ZiprasidoneshouldnotbegiventogetherwithmedicinalproductsthatareknowntoprolongtheQTinterval(see

section4.3and4.5).Cautionisadvisedinpatientswithsignificantbradycardia.Electrolytedisturbancessuchas

hypokalaemiaandhypomagnesaemiaincreasetheriskformalignantarrhythmiasandshouldbecorrectedbefore

treatmentwithziprasidoneisstarted.Ifpatientswithstablecardiacdiseasearetreated,anECGreviewshouldbe

consideredbeforetreatmentisstarted.

Ifcardiacsymptomssuchaspalpitations,vertigo,syncopeorseizuresoccur,thenthepossibilityofamalignantcardiac

arrhythmiashouldbeconsideredandacardiacevaluation,includinganECGshouldbeperformed.IftheQTc-interval

is>500msec,thenitisrecommendedthatthetreatmentshouldbestopped(seesection4.3).

Therehavebeenrarepost-marketingreportsoftorsadedepointesinpatientswithmultipleconfoundingriskfactors

takingziprasidone.

Childrenandadolescents

Thesafetyandefficacyofziprasidoneintramuscularinjectionhasnotbeenevaluatedinchildrenandadolescents.

Elderly(>65years)

Elderlypatientshavenotbeenincludedinclinicaltrialsinsufficientnumbers.Thus,norecommendationsasregards

dosingcouldbegivenandintramusculartreatmentinthesepatientsisnotrecommended.

Neurolepticmalignantsyndrome(NMS)

NMSisararebutpotentiallyfatalcomplexthathasbeenreportedinassociationwithotherantipsychoticmedicinal

products,includingziprasidone.ThemanagementofNMSshouldincludeimmediatediscontinuationofall

antipsychoticmedicinalproducts.

Cardiovasculardisease

Patientswithcardiovasculardiseasehavenotbeenincludedintheclinicaltrialsinsufficientnumbers.Thus,thesafe

useoftheintramuscularproducthasnotbeenestablished(seesection4.3).

Bloodpressure

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ziprasidone.Singlecasesofhypertensionhavealsobeenreported.Cautionshouldbeexercised,particularlyin

ambulatorypatients.

Seizures

Cautionisadvisedwhentreatingpatientswithahistoryofseizures.

HepaticImpairment

Thereisalackofexperienceinpatientswithseverehepaticinsufficiencyandziprasidoneshouldbeusedwithcaution

inthisgroup(seesection4.2and5.2).

Increasedriskofcerebrovascularaccidentsinthedementiapopulation

Anapproximately3-foldincreasedriskofcerebrovascularadverseeventshasbeenseeninrandomisedplacebo-

controlledclinicaltrialsinthedementiapopulationwithsomeatypicalantipsychotics.Themechanismforthis

increasedriskisnotknown.Anincreasedriskcannotbeexcludedforotherantipsychoticsorotherpatientpopulations.

Geodonshouldbeusedwithcautioninpatientswithriskfactorsforstroke.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

PharmacokineticandpharmacodynamicstudiesbetweenziprasidoneandothermedicinalproductsthatprolongtheQT

intervalhavenotbeenperformed.Anadditiveeffectofziprasidoneandthesemedicinalproductscannotbeexcluded,

thereforeziprasidoneshouldnotbegivenwithmedicinalproductsthatprolongtheQTinterval,suchasClassIAand

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

sparfloxacin,gatifloxacin,moxifloxacin,dolasetronmesilate,mefloquine,sertindoleorcisapride(seesection4.3)

CNSmedicinalproducts/alcohol

Giventheprimaryeffectsofziprasidone,cautionshouldbeusedwhenitistakenincombinationwithothercentrally

actingmedicinalproductsandalcohol.

Effectofziprasidoneonothermedicinalproducts

Allinteractionstudieshavebeenconductedwithoralziprasidone.

AninvivostudywithdextromethorphanshowednomarkedinhibitionofCYP2D6atplasmaconcentrations50%lower

thanthoseobtainedafter40mgziprasidonetwicedaily.Invitrodataindicatedthatziprasidonemaybeamodest

inhibitorofCYP2D6andCYP3A4.However,itisunlikelythatziprasidonewillaffectthepharmacokineticsof

medicinalproductsmetabolisedbythesecytochromeP450isoformstoaclinicallyrelevantextent.

Oralcontraceptives-Ziprasidoneadministrationresultedinnosignificantchangetothepharmacokineticsofoestrogen

(ethinyloestradiol,aCYP3A4substrate)orprogesteronecomponents.

Lithium-Co-administrationofziprasidonehadnoeffectonthepharmacokineticsoflithium.

Effectsofothermedicinalproductsonziprasidone

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

serumconcentrationsofS-methyl-dihydroziprasidoneandziprasidonesulphoxide,attheexpectedTmaxof

ziprasidone,wereincreasedby55%and8%respectively.NoadditionalQTcprolongationwasobserved.Changesin

pharmacokineticsduetocoadministrationofpotentCYP3A4inhibitorsareunlikelytobeofclinicalimportance,

thereforenodosageadjustmentisrequired.

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

ziprasidone.

Antacid–multipledosesofaluminiumandmagnesiumcontainingantacidorcimetidinehavenoclinicallysignificant

effectonthepharmacokineticsofziprasidoneunderfedconditions.

Serotonergicmedicinalproducts

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ziprasidoneincombinationwithotherserotonergicmedicinalproductssuchasSSRIs(seesection4.8).Thefeaturesof

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

4.6Fertility,pregnancyandlactation

Reproductivetoxicitystudieswithziprasidonehaveshownundesirableeffectsonthereproductiveprocess,atdoses

associatedwithmaternaltoxicityand/orsedation.

Therewasnoevidenceofteratogenicity(seesection5.3).

Useinpregnancy

Nostudieshavebeenconductedinpregnantwomen.Womenofchildbearingpotentialshouldthereforebeusingan

appropriatemethodofcontraception.Ashumanexperienceislimited,administrationofziprasidoneisnot

recommendedduringpregnancyunlesstheexpectedbenefittomotheroutweighsthepotentialrisktothefoetus.

Useinlactation

Itisnotknownwhetherziprasidoneisexcretedinbreastmilk.Patientsshouldnotbreastfeediftheyarereceiving

ziprasidone.Iftreatmentisnecessary,breast-feedingshouldbediscontinued.

4.7Effectsonabilitytodriveandusemachines

Ziprasidonemaycausesomnolenceandmayinfluencetheabilitytodriveandusemachines.Patientslikelytodriveor

operatemachinesshouldbecautionedappropriately.

4.8Undesirableeffects

Ziprasidoneintramuscular

Thetablebelowcontainsadverseeventswithpossible,probableorunknownrelationshiptoziprasidoneinphase2/3

trials.Themostcommonreactionswerenausea,sedation,dizziness,injectionsitepain,headacheandsomnolence.

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

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

Theadversereactionslistedbelowmayalsobeassociatedwiththeunderlyingdiseaseand/orconcomitantmedications.

BodySystem Adversedrugreactions

Metabolismandnutritiondisorders

Uncommon Anorexia

Psychiatricdisorders

Uncommon Agitation,antisocialbehaviour,psychoticdisorder,insomnia,tic

Nervoussystemdisorders

Common Akathisia,dizziness,dystonia,headache,sedation,somnolence

Uncommon Cogwheelrigidity,dizzinesspostural,dysarthria,dyskinesia,dyspraxia,

parkinsonism,tremor

Cardiacdisorders

Uncommon Bradycardia,tachycardia

Earandlabyrinthdisorders

Uncommon Vertigo

Vasculardisorders

Common Hypertension

Uncommon Flushing,orthostatichypotension

Respiratory,thoracicandmediastinaldisorders

Uncommon Laryngospasm

Gastrointestinaldisorders

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Themostcommoncardiovascularadverseeventsreportedfromfixeddoseclinicaltrialswithintramuscularziprasidone

were:dizziness(10mg-11%,20mg–12%),tachycardia(10mg-4%,20mg–4%)andposturaldizziness(10mg–

2%,20mg–2%),orthostatichypotension,20mg–5%)andhypotension(10mg–2%).

Inpremarketingfixeddoseclinicaltrialswithziprasidoneintramuscularinjection,increasedbloodpressureand

hypertensionwereobservedin2.2%ofpatientsreceiving10mgandincreasedbloodpressurewasobservedin2.8%of

patientsreceiving20mg.

Ziprasidonecapsules

Oralziprasidonehasbeenadministeredinclinicaltrials(seesection5.1)toapproximately6500subjects.Themost

commonadversereactionsinschizophreniaclinicaltrialsweresedationandakathisia.Inbipolarmaniaclinicaltrials,

themostcommonadversereactionsweresedation,akathisia,extrapyramidaldisorderanddizziness.

Thetablebelowcontainsadverseeventsbasedoncombinedshortterm(4-6week),fixeddose,schizophreniastudies

andshortterm(3week),flexibledose,bipolarmaniastudieswithaprobableorpossiblerelationshiptotreatmentwith

ziprasidoneandwhichoccuratanincidencegreaterthanplacebo.

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

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

Uncommon Constipation,diarrhoea,loosestools,drymouth

Skinandsubcutaneoustissuedisorders

Uncommon Hyperhidrosis

Musculoskeletalandconnectivetissuedisorders

Common Musclerigidity

Generaldisordersandadministrationsiteconditions

Common Asthenia,Injectionsiteburning,Injectionsitepain

Uncommon Drugwithdrawalsyndrome,fatigue,influenzalikeillness,injectionsite

discomfort,injectionsiteirritation

Investigations

Uncommon Bloodpressuredecreased,hepaticenzymeincreased

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

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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.

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

Rare Systolichypertension,diastolichypertension,labilebloodpressure

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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weresometimeselevated,but,inmostpatients,returnedtonormalrangeswithoutcessationoftreatment.Inaddition,

potentialclinicalmanifestations(e.g.gynaecomastiaandbreastenlargement)wererare.

PostMarketing:

Thefollowingtableofadverseeventsisbasedonreportsfrompostmarketingexperience:

4.9Overdose

Experiencewithziprasidoneinoverdoseislimited.Thelargestconfirmedsingleingestionofziprasidoneis12,800mg.

Inthiscase,extrapyramidalsymptomsandaQTcintervalof446msec(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,12hoursafterasingleoraldoseof40mg,wasgreaterthan80%forserotonintype2

andgreater

than50%forD

usingpositronemissiontomography(PET).Ziprasidonealsointeractswithserotonin5HT

,5HT

and5HT

receptorswhereitsaffinitiesforthesesitesareequaltoorgreaterthanitsaffinityfortheD

receptor.

Ziprasidonehasmoderateaffinityforneuronalserotoninandnorepinephrinetransporters.Ziprasidonedemonstrates

moderateaffinityforhistamineH(1)-andalpha(1)-receptors.Ziprasidonedemonstratesnegligibleaffinityfor

muscarinicM(1)-receptors.

Ziprasidonehasbeenshowntobeanantagonistatbothserotonintype2

(5HT

)anddopaminetype2(D

receptors.Itisproposedthattheantipsychoticactivityismediated,inpart,throughthiscombinationofantagonist

activities.Ziprasidoneisalsoapotentantagonistat5HT

and5HT

receptors,apotentagonistatthe5HT

SystemOrganClass Adversedrugreactions

Immunesystem

disorders Anaphylacticreaction

Psychiatricdisorders Insomnia;mania/hypomania

NervousSystem

Disorders Neurolepticmalignantsyndrome;serotoninsyndrome(seesection4.5);

facialdroop

Cardiacdisorders Torsadedepointes(seesection4.4)

Vasculardisorders Syncope

Skinand

subcutaneousTissue

Disorders Hypersensitivity,Angioedema

RenalandUrinary

disorders Enuresis

Reproductivesystem

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Furtherinformationonclinicaltrials

Inclinicaltrials,thesafetyandtolerabilityofintramuscularinjectionandsubsequentcontinuationwithoraltherapy

wasdemonstrated.

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.

5.2Pharmacokineticproperties

Absorption:Thebioavailabilityofziprasidoneadministeredintramuscularlyis100%.Afterintramuscular

administrationofsingledoses,peakserumconcentrationstypicallyoccuratapproximately30-60minutespost-dose.

Exposureincreasesinadose-relatedmannerandfollowing3daysofintramusculardosing,littleaccumulationis

observed..

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

serum.

Biotransformationandelimination:Themeanterminalhalf-lifeonthethirddayofdosingrangedfrom8to10hours.

Themeanterminalhalf-lifeofziprasidoneafterintravenousadministrationis6hours.Meanclearanceofziprasidone

administeredintravenouslyis5ml/min/kg.Approximately20%ofthedoseisexcretedinurine,andapproximately

66%iseliminatedinfaeces.

Ziprasidoneisextensivelymetabolisedafteroraladministrationwithonlyasmallamountexcretedinurine(<1%)or

faeces(<4%)asunchangeddrug.Ziprasidoneisprimarilyclearedviathreeproposedmetabolicroutestoyieldfour

majorcirculatingmetabolites,benzisothiazolepiperazine(BITP)sulphoxide,BITPsulphone,ziprasidonesulphoxide

andS-methyl-dihydroziprasidone.Unchangedziprasidonerepresentsabout44%oftotaldrug-relatedmaterialin

serum.

AninvivostudysuggeststhatconversiontoS-methyldihydroziprasidoneisthemajorrouteofmetabolismfor

ziprasidone.Invitrostudiesindicatethatthismetabolitearisesviaaldehydeoxidasecatalysedreduction,with

subsequentS-methylation.Oxidativemetabolism,principallyviaCYP3A4withpotentialcontributionofCYP1A2,is

alsoinvolved.

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

maypredictaQTc-prolongingeffect.S-methyl-dihydroziprasidoneismainlyeliminatedinfaecespresumablyby

biliaryexcretionwithaminorcontributionbyCYP3A4catalysedmetabolism.Ziprasidonesulphoxideiseliminated

throughrenalexcretionandbysecondarymetabolismcatalysedbyCYP3A4.

Specialpopulations:

Pharmacokineticscreeningofpatientstreatedorallyhasnotrevealedanysignificantpharmacokineticdifferences

betweensmokersandnon-smokers.

Noclinicallysignificantage-orgender-differencesinthepharmacokineticswereobservedfollowingoral

administration.

Consistentwiththefactthatrenalclearancecontributesverylittletoitsoverallclearance,noprogressiveincreasesin

ziprasidoneexposurewerenotedwhenziprasidonewasadministeredtosubjectswithvaryingdegreesofrenalfunction.

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

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ml/min)followingoraladministrationof20mgBIDforsevendays.Itisunknownwhetherserumconcentrationsof

themetabolitesareincreasedinthesepatients.

Inmildtomoderateimpairmentofliverfunction(ChildPughAorB)causedbycirrhoses,theserumconcentrations

afteroraladministrationwere30%higherandtheterminalhalf-lifewasabout2hourslongerthaninnormalpatients.

Theeffectofliverimpairmentonserumconcentrationsofthemetabolitesisunknown.

5.3Preclinicalsafetydata

Preclinicalsafetydataonziprasidoneadministeredorallyrevealnospecialhazardforhumansbasedonconventional

studiesofsafetypharmacology,genotoxicityandcarcinogenicpotential.Inreproductivestudiesinratsandrabbits,

ziprasidonehasshownnoevidenceofteratogenicity.Undesirableeffectsonfertilityanddecreasedpupweightswere

observedatdosescausingmaternaltoxicitysuchasdecreasedbodyweightgain.Increasedperinatalmortalityand

delayedfunctionaldevelopmentofoffspringoccurredatmaternalplasmaconcentrationsextrapolatedtobesimilarto

themaximalconcentrationsinhumansgiventherapeuticdoses.

Inparenteralstudiesofziprasidonetherewerenoadversefindingsrelevanttotheclinicaluseoftheproduct.

Skeletalvariations,butnomalformations,wereobservedinarabbitteratologystudyoftheexcipientSBECD.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Powder:Sulphobutyletherbeta-cyclodextrinsodium.

Solvent:WaterforInjections.

6.2Incompatibilities

ThismedicinalproductmustnotbemixedwithothermedicinalproductsorsolventsexceptWaterforInjections

mentionedinSection6.6.

6.3ShelfLife

3years.

Chemicalandphysicalin-usestabilityofthereconstitutedproducthasbeendemonstratedfor24hoursupto25 °

Cand

7daysat2to8 °

C.Howeverfromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotused

immediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynot

belongerthan24hoursat2to8 °

C,unlessreconstitutionhastakenplaceincontrolledandvalidatedaseptic

conditions.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

Keepcontainerintheoutercarton.

Donotfreeze.

6.5Natureandcontentsofcontainer

Type1flintglassvialscontainingpowder(ziprasidonemesilate).Thevialsaresealedwithbutylrubberlyophile

stoppersandflip-offaluminiumseals.

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Packsize:1vialand1ampoulepercarton

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Thecontentsofthevial(powder)shouldbereconstitutedbyintroductionof1.2mlofthesuppliedWaterforInjections

(solvent),affordingaconcentrationof20mgziprasidoneperml,andshakinguntilcompletedissolutionhasoccurred.

Onlyclearsolutions,freeofvisibleparticles,shouldbeused.Onlyonedose(0.5mlcorrespondingto10mg

ziprasidone,or1mlcorrespondingto20mgziprasidone)shouldbewithdrawnfromeachvialandtheremainder

discarded.

7MARKETINGAUTHORISATIONHOLDER

PfizerLimited

RamsgateRoad

Sandwich

Kent

CT139NJ

8MARKETINGAUTHORISATIONNUMBER

PA19/52/5

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:08March2002

Dateoflastrenewal:01August2005

10DATEOFREVISIONOFTHETEXT

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