FLUOXETINE

Main information

  • Trade name:
  • FLUOXETINE Oral Solution 20mg/5ml MG/5ml
  • Dosage:
  • 20mg/5ml MG/5ml
  • Pharmaceutical form:
  • Oral Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUOXETINE Oral Solution 20mg/5ml MG/5ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0281/114/001
  • Authorization date:
  • 13-11-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0281/114/001

CaseNo:2049123

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PinewoodLaboratoriesLtd

Ballymacarbry,Clonmel,Co.Tipperary,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Fluoxetine20mg/5mlOralSolution

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom11/12/2008until12/11/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fluoxetine20mg/5mlOralSolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlcontains20mgfluoxetine(ashydrochloride).

Forexcipientssee6.1

3PHARMACEUTICALFORM

OralSolution

Aclear,colourlesssolutionwithapeppermintodour.

4CLINICALPARTICULARS

4.1TherapeuticIndications

a)Majordepressiveepisodes

b)Bulimianervosa:Fluoxetineisindicatedasacomplementofpsychotherapyforthereductionofbinge-eatingand

purgingactivity.

c)Obsessive-compulsivedisorder.

4.2Posologyandmethodofadministration

Fororaladministration

Fluoxetinemaybetakenwithorwithoutfood.

a)Majordepressiveepisodes:Studieshaveshownthat20mg/dayissufficienttoachieveasatisfactoryresponsein

mostpatients.Itisrecommendedthatdosesofmorethan20mgperdayshouldbegivenintwodivideddailydoses.

Thisdosemaybeincreasedgraduallyto60mgdailyifnecessary.Agradualdoseincreaseshouldbeconsideredonlyif

noimprovementisobservedafter2-4weeks.

InagreementwiththeconsensusstatementoftheWHO,antidepressantmedicationshouldbecontinuedforatleast6

months.

b)Bulimianervosa:Adoseof60mg/dayisrecommended.

Long-termefficacy(morethan3months)hasnotbeendemonstratedinbulimianervosa.Thedosecantentativelybe

dividedinamorningandafternoondoseiftroublesomeadverseeventsappear.

c)Obsessive-compulsivedisorder–adultsandtheelderly:20mg/dayto60mg/day.Adoseof20mg/dayis

recommendedastheinitialdose.Althoughtheremaybeanincreasedpotentialforside-effectsathigherdoses,adose

increasemaybeconsideredaftertwoweeksifthereisnoresponse.Ifnoimprovementisobservedwithin10weeks,

treatmentwithfluoxetineshouldbereconsidered.Ifagoodtherapeuticresponsehasbeenobtained,treatmentcanbe

continuedatadosageadjustedonanindividualbasis.Whiletherearenosystemicstudiestoanswerthequestionof

howlongtocontinuefluoxetinetreatment,OCDisachronicconditionanditisreasonabletoconsidercontinuation

beyond10weeksinrespondingpatients.Dosageadjustmentsshouldbemadecarefullyonanindividualpatientbasis,

tomaintainthepatientatthelowesteffectivedose.Theneedfortreatmentshouldbereassessedperiodically.Some

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Longtermefficacy(morethan24weeks)hasnotbeendemonstratedinOCD.

d)Allindications

Themaximumdailydoseshouldnotexceed80mg.

Whendosingisstopped,activedrugsubstanceswillpersistinthebodyforweeks.Thisshouldbeborneinmindwhen

startingorstoppingtreatment.Fluoxetinedosagetaperingisusuallyunnecessaryinmostpatients.

Elderlypatients:

Cautionisrecommendedwhenincreasingthedoseandthedailydoseshouldgenerallynotexceed40mg.Maximum

recommendeddoseis60mg/day.

Children:Notrecommended.ThesafetyandefficacyofFluoxetineinchildrenandadolescentshasnotbeen

established.

Hepaticdysfunction:

Alowerorlessfrequentdose(e.g.20mgeverysecondday)shouldbeconsideredinpatientswithhepaticimpairment

(see5.2Pharmacokineticproperties)orinpatientswhereconcomitantmedicationhasthepotentialforinteraction(see

4.5Interactions).

4.3Contraindications

Fluoxetineiscontraindicatedfor

a)Patientswithhypersensitivitytotheactivefluoxetineoranyoftheexcipientsstatedinsection6.1.

b)Fluoxetineshouldnotbetakenconcomitantlywithmonoamineoxidaseinhibitors(MAOinhibitors),namely

irreversiblenon-selectiveandB-selectiveMAOinhibitorsandreversibleA-selectiveMAOinhibitors.

Itisrecommendedthatatleast14daysshouldelapsebetweendiscontinuationofanMAOIandinitiationof

treatmentwithFluoxetine.Atleastfiveweeks(longerifFluoxetinehasbeenprescribedchronicallyand/orata

higherdose)shouldelapsebetweendiscontinuationofFluoxetineandinitiationofMAOItherapy.Iffluoxetineis

takenforalongtimeand/oratahighdose,alongerperiodmaybeconsidered.

Therehavebeenreportedcaseswithfeaturesresemblingserotoninsyndrome,whichmayresembleandbediagnosedas

neurolepticmalignantsyndromeinpatientstreatedwithfluoxetineandaMAOinhibitorinclosetemporalproximity.

(c.f.section4.5Interactionwithothermedicamentsandotherformsofinteraction).

4.4Specialwarningsandprecautionsforuse

a)FluoxetinecontainsBenzoicacid,whichisamildirritanttotheskin,eyesandmucousmembrane.

b)FluoxetinecontainsGlycerol,whichmaycauseheadache,upsetstomachanddiarrhoea.

c)Fluoxetinecontains3gofsucroseper5ml.Whentakenaccordingtodosagerecommendations,themaximumdaily

doseoffluoxetineoralsolutionmayprovideupto12gofsucrose.Unsuitableforhereditaryfructoseintolerance,

glucose-galactosemalabsorptionsyndromeandsucrase-isomaltasedeficiency.

d)Suicide/suicidalthoughtsorclinicalworsening:Depressionisassociatedwithanincreasedriskofsuicidalthoughts,

selfharmandsuicide(suicide-relatedevents).Thisriskpersistsuntilsignificantremissionoccurs.Asimprovement

maynotoccurduringthefirstfewweeksormoreoftreatment,patientsshouldbecloselymonitoreduntilsuch

improvementoccurs.Itisgeneralclinicalexperiencethattheriskofsuicidemayincreaseintheearlystagesof

recovery.

Otherpsychiatricconditionsforwhichfluoxetineisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybecomorbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

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commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

e)Rash:RashandotherallergicreactionshavebeenreportedtooccurduringtreatmentwithFluoxetine.Someofthese

reactionsare:skinrashes,urticaria,anaphylactoideventsaswellasprogressivesystemicevents(skin,kidney,liverand

lung).Upontheappearanceofrashorofotherpossibleallergicphenomenaforwhichanalternativeaetiologycannot

beidentified,fluoxetineshouldbediscontinued.

f)Seizures:Aswithotherantidepressants,fluoxetineshouldbeusedwithcautioninpatientswithaprevioushistoryof

seizures.Treatmentshouldbediscontinuedinanypatientwhodevelopsseizures.Fluoxetineshouldbeavoidedin

patientswithunstableoruncontrolledepilepsy.Patientswithcontrolledepilepsyshouldbecarefullymonitored.

g)Hepaticandrenalfunction:AsFluoxetineisextensivelymetabolisedbytheliverandexcretedbythekidneys,

cautionshouldbeexercisedinpatientswithimpairedrenaland/orhepaticfunction(seeunder4.2Posology).

h)Diabetesmellitus:Fluoxetinehasbeenreportedtoalterbloodglucosecontrolinpatientswithdiabetes.

Hypoglycaemiahasoccurredduringtherapywithfluoxetineandhyperglycaemiahasdevelopedfollowing

discontinuationoftherapy.Itisthereforerecommendedthatthedosageofinsulinand/ororalantidiabeticsshouldbe

monitoredandwherenecessaryadjustedwhentherapywithfluoxetineisinitiatedordiscontinued.

i)Mania:Aswithallantidepressants,careshouldbeusedwhenprescribingFluoxetinetopatientswhohaveahistory

ofhypomaniaormania.TreatmentwithFluoxetineshouldbediscontinuedwiththepatiententeringthemanicphase.

j)Cardiacdisease:Clinicalexperiencewithacutecardiacdiseaseislimited,thereforecautionisadvisable.

k)Bodyweight:Overweightpatientsgenerallyexperienceweightlossduringtreatmentwithfluoxetine.Patientswitha

normalbodyweightusuallyexperiencelittleornoweightloss.Inpatientswithanorexiaitisrecommendedthatbody

weightshouldbemonitoredregularlyduringtreatmentwithfluoxetine.

Clinicaltrialsrelatingtothetreatmentofbulimianervosahaveshownthatnopatientshavediscontinuedtreatmentasa

resultofreductioninbodyweight(seesection4.8Undesirableeffects).

l)Haemorrhage:Cautionshouldbeusedinpatientswhoarereceivingmedicationwhichaltersplateletfunction,as

fluoxetinehasbeenknowntocausecutaneousbleedingabnormalitiessuchaspurpurawhileecchymosishasbeen

infrequentlyreported.Therehavealsobeenrarereportsofotherhaemorrhagicmanifestationssuchas:gynaecological

haemorrhaging,gastro-intestinalhaemorrhagingandothermucousandcutaneousbleedings.Cautionisadvisedin

patientstakingSSRI’s,particularlyinconcomitantusewithoralanticoagulants,drugsknowntoaffectplateletfunction

(e.g.atypicalantipsychoticssuchasclozapine,phenothiazines,mostTCA’s,acetylsalicylicacid,NSAIDs)orother

drugsthatmayincreasetheriskofbleedingaswellasinpatientswithahistoryofbleedingdisorders.

m)Hyponatraemia:Severalcasesofhyponatraemia(somewithsodiumlevelslowerthan110mmol/l)havebeen

reported.Theprocesshasbeenshowntobereversible.Althoughthesecaseswerecomplexwithvaryingaetiologies,in

sometherewereindicationsoftheSIADHsyndrome(syndromeofinappropriateantidiuretichormonesecretion).The

majorityofthesecasesoccurredinelderlypatientsandinpatientstreatedwithdiureticsorotherwisevolume-depleted.

n)ElectroconvulsiveTherapy(ECT):Therehavebeenrarereportsofprolongedseizuresinpatientsonfluoxetine

receivingECTtreatment,thereforecautionisadvisable.

o)StJohn'sWort:Anincreaseinserotonergiceffects,suchasserotoninsyndrome,mayoccurwhenselectiveserotonin

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p)Serotoninsyndrome:Onrareoccasionsdevelopmentofaserotoninsyndromeorneurolepticmalignantsyndrome-

likeeventshavebeenreportedinassociationwithtreatmentoffluoxetine,particularlywhengivenincombinationwith

otherserotonergic(amongothersL-tryptophan)and/orneurolepticdrugs.Asthesesyndromesmayresultinpotentially

life-threateningconditions,treatmentwithfluoxetineshouldbediscontinuedifsuchevents(characterisedbyclustersof

symptomssuchashyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvital

signs,mentalstatuschangesincludingconfusion,irritability,extremeagitationprogressingtodeliriumandcoma)

occurandsupportivesymptomatictreatmentshouldbeinitiated.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Eliminationhalf-life:Thelongeliminationhalf-livesoffluoxetineanditsprincipalmetabolitenorfluoxetineareof

potentialconsequencewhenmedicinesareprescribedwhichmightinterferewitheithersubstancefollowingthe

discontinuationoftreatmentwithfluoxetine.

Contraindicatedcombinations

MAOinhibitors:Therehavebeenreportsofserious,sometimesfatalreactions(includinghypothermia,rigidity,

myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvitalsignsandmentalstatuschangesthatinclude

extremeagitationprogressingtodeliriumandcoma)inpatientsreceivingfluoxetineincombinationwithamonoamine

oxidaseinhibitor(MAOI),andinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonanMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndromewhichmayresembleandbediagnosedas

neurolepticmalignantsyndrome(see4.3Contraindications).Oralcyprohepatidineorintravenousdantrolenemaybeof

benefittopatientsexperiencingsuchreactions.Atleast14daysshouldelapsebetweendiscontinuationofaMAOIand

initiationoftreatmentwithfluoxetine.

Sincefluoxetineanditsactivemetabolitehaveverylongeliminationhalf-livesatleast5weeks(approximately5half-

livesofnorfluoxetine)shouldbeallowedafterstoppingfluoxetinebeforestartingaMAOI.

Combinationsrequiringprecautionsforuse

Oralanticoagulants:Alteredanticoagulanteffects(laboratoryvaluesand/orclinicalsignsandsymptoms),withno

consistentpatternbutwithanincreasedtendencytobleeding,havebeenreporteduncommonlywhenfluoxetineis

coadministeredwithwarfarin.Asisprudentinconcomitantuseofwarfarinwithmanyothermedicines,thesepatients

shouldalsobemonitoredwithrespecttotheircoagulationtimeswhentreatmentwithfluoxetineisinitiatedor

discontinued.

Lithiumandtryptophan:TherehavebeenreportsofserotoninsyndromewhenSSRIshavebeengivenwithlithiumor

tryptophansocareshouldbeexercisedwhenbeingadministeredconcurrentlywithfluoxetine.Whenfluoxetineisused

incombinationwithlithium,closerandmorefrequentclinicalmonitoringisrequired.

MedicinesmetabolisedbyCYP2D6:FluoxetinecaninhibittheactivityofthecytochromeP450iso-enzyme2D6

(CYP2D6).Forthisreason,therapywithmedicationsthatarepredominantlymetabolisedbyCYP2D6andthathavea

relativelynarrowtherapeuticindexshouldbeinitiatedatthelowendoftherecommendeddosagerangeifthepatientis

receivingfluoxetineconcurrentlyorhastakenitinthepast5weeks.Iffluoxetineisaddedtothemedicationofa

patientalreadyreceivingadrugthatismetabolisedbyCYP2D6,thentheneedtodecreasethedoseoftheoriginal

medicationshouldbeconsidered.Thisisparticularlyimportantindrugswithanarrowtherapeuticindexsuchas

flecainide,encainide,vinblastine,carbamazepineandtricyclicantidepressants.

CNSactivemedicines:Fluoxetine,whentakenconcurrentlywithCNSactivemedication,maycausechangesinthe

bloodlevelsofcarbamazepine,haloperidol,clozapine,diazepam,alprazolam,lithium,phenytoinandcyclic

antidepressants(e.g.imipramineanddesipramine).Therehavebeencaseswheretoxicityhasbeenobserved.Itmaybe

necessarytouseconservativetitrationschedulesoftheconcomitantmedicineandtomonitorclinicalstatus.

Serotonergicdrugs:Co-administrationwithserotonergicdrugs(e.g.tramadol,triptans)mayincreasetheriskof

serotoninsyndrome.Usewithtriptanscarriestheadditionalriskofcoronaryvasoconstrictionandhypertension.

Proteinbindingdrugs:Becausefluoxetineishighlyboundtoplasmaproteins,competitioninrespectofproteinbinding

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bechanged.

ElectroConvulsiveTreatment:TherehavebeenrarereportsofprolongedseizuresinpatientsreceivingECTtreatment,

whiletakingfluoxetine.

Alcohol:Informaltesting,fluoxetinedidnotraisebloodalcohollevelsorenhancetheeffectsofalcohol.However,the

combinationofSSRItreatmentandalcoholarenotadvisable.

St.John’sWort:FluoxetinecanpharmacodynamicallyinteractwiththeherbalremedySt.John’sWort(Hypericum

perforatum),causinganincreaseinundesirableeffects.

4.6Pregnancyandlactation

a)Pregnancy:Dataonalargenumberofexposedpregnanciesdonotindicateateratogeniceffectoffluoxetine.

Fluoxetinecanbeusedduringpregnancy,butcautionshouldbeexercised,especiallyduringlatepregnancyorjust

priortotheonsetoflaboursincethefollowingeffectshavebeenreportedinneonates:irritability,tremor,hypotonia,

persistentcrying,difficultyinsuckingorsleeping.Thesesymptomsmayindicateeitherserotonergiceffectsora

withdrawalsyndrome.Thetimetooccurandthedurationofthesesymptomsmayberelatedtothelonghalflifeof

fluoxetine(4–6days)anditsactivemetabolite,norfluoxetine(4–16days).

b)Lactation:Fluoxetineanditsmetabolitenorfluoxetine,areknowntobeexcretedinhumanbreastmilk.Adverse

eventshavebeenreportedinbreastfeedinginfants.Iftreatmentwithfluoxetineisconsiderednecessary,discontinuation

ofbreastfeedingshouldbeconsidered;however,ifbreastfeedingiscontinued,thelowesteffectivedoseoffluoxetine

shouldbeprescribed.

4.7Effectsonabilitytodriveandusemachines

Fluoxetinehasnoeffectonpsychomotorfunctioninhealthyvolunteers.Allpsycho-activemedicineshowever,may

impairjudgementandreactiontime.Patientsshouldbeadvisedtoavoiddrivingvehiclesorusingmachinesuntilitis

certainthatfluoxetinedoesnotaffectperformance.(c.f.4.8Undesirableeffects).

4.8Undesirableeffects

Themostfrequentundesirableeffectsaremostlyperceivedatthebeginningofthetreatmentandasaruletheyare

alleviatedasthetreatmentperiodproceeds.

Bodyasawhole:

Common:chills,increasedperspiration

Centralnervoussystem:

Verycommonundesirableeffects:Undesirableeffectsstemmingfromthecentralnervoussystem,suchasheadaches,

insomnia,anxiety,exhaustion,nervousness,dizziness,tremors,impotence,mentalconfusion,paresthesiaand

nightmares.Ingeneraltheseundesirableeffectsareofapassingnature.

Commonundesirableeffects:Thefluoxetinetreatmentmaycausesuddenhypomaniaandmaniainpatientswhosuffer

frombipolaraffectivedisorders.

Rareundesirableeffects:Dyskinesia,movementdisordersdevelopinginpatientswithriskfactors(includingdrugs

associatedwithsuchevents)andworseningofpre-existingmovementdisorders,andneurolepticmalignantsyndrome-

Frequencyestimates: Verycommon ( ≥10%)

Common

≥1%-<10%)

Uncommon

≥0.1%-<1%)

Rare

≥0.01%-<0.1%)

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Extrapyramidalmotoricsymptomsmayoccurortheymaygrowstrongerespeciallyinpatientsthataresensitivetosuch

symptoms(e.g.patientssufferingfromParkinson'sDisease).

Patientsthat,inadditiontofluoxetine,receiveelectroconvulsivetreatment(ECT)haveinsporadiccasesbeenknown

tosufferfromseizuresandextendedperiodsofseizures.

Digestivesystem:

Verycommonundesirableeffects:Undesirableeffectsconnectedtothedigestivesystemsuchasnausea,dryingofthe

mouth,diarrhoea,constipation,lossofappetite,vomiting,stomachpains,flatulenceandchangestothesenseoftaste.

Weightlossmayoccurinpatientstakingfluoxetinebutitisusuallyproportionaltobaselinebodyweight.However,

onlyrarelyhavepatientsdiscontinuedtreatmentwithfluoxetinebecauseofanorexiaorweightloss.

Uncommonundesirableeffects:Differentdegreesofliverdisordershavebeenreported.Anincreaseoftheliver

enzymevaluesisalsopossible,althoughthesechanges,inmostinstances,arenormalisedoncethetreatmentis

discontinued.

Rareundesirableeffects:Inrarecasesidiosyncratichepatitishasbeenobserved.

SkinandAppendages:

Commonundesirableeffects:Pruritis,rashandurticaria,exceptionallyQuinckeoedema,Anaphylacticreactions

includingbronchospasm,angioneuroticoedemaandurticaria:reactionsoftheskinlinkedwithfever,leucocytosis,pain

inthejoints,dyspnoeamightoccur.Thesecommonsymptomsmayalsobeobservedwithoutsimultaneousreactionsof

theskin.Whenreactionsoftheskinorotherpossibleallergicreactionsoccur,thefluoxetinetreatmentshouldbe

discontinued.

Rareundesirableeffects:Vasculitis,erythemapolymorph,orexceptionallyLyellsyndrome,andrarecasesoffeverand

arthralgiaasinserumsickness.Serotoninsymptomcomplexhaveoccasionallybeenreported.Inconnectionwith

dermalreactionsserioussystemiclung,kidneyorliverreactionshavebeenobservedinsomepatients.Thesereactions

maybeconnectedtoavascularinflammation.Thesesystemicreactionsareextremelyrare,butonefatalcasehasbeen

reported.

SpecialSenses:

Commonundesirableeffect:Visualdisorders.Insomepatients,anincreaseofocularpressurehasbeenobserved.

Thoseundesirableeffectsarenormalizedoncethetreatmentisdiscontinued.

CardiovascularSystem:

Uncommonundesirableeffects:Increasedanddecreasedbloodpressureaswellasfaintinghaveoccurred.Small

increaseindiastolicbloodpressureandtachycardiaaswellasbradycardiahasbeenreported.

EndocrineSystem:

Uncommonundesirableeffects:Hypo-orhyperthyroidismmayoccur.Afterthediscontinuationofthetreatment

reversiblehyponatraemia(<110mmol/l)hasbeenobserved,mainlyinelderlypatients,andinpatientswhohave

receiveddiureticsorpatientssufferingfromlossofbodywater.

HemicandLymphaticSystem:

Uncommonundesirableeffects:Ecchymosis,dermal,gastrointestinalornasalbleeding.

Therehavebeenreportsofabnormalbleedinginseveralpatients,butcasualrelationshiptofluoxetineandclinical

importanceareunclear.

Rareundesirableeffects.Leucopeniaispossible,althoughthischange,inmostinstances,isnormalisedoncetreatment

isdiscontinued.

RespiratorySystem:

Rareundesirableeffects:Pharyngitis,coughanddyspnoea.Pulmonaryabnormalitieshavebeenreportedrarely.In

sporadiccasesinflammatoryorfibrioticchangesinthelungshavebeenobserved,theonlysymptomofwhichhasbeen

dyspnoea.

UrogenitalSystem:

Commonundesirableeffect:disordersofthesexualfunctionsincludingdelayedorgasm,anorgasmbothinmanandin

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SpecialPrecautions:

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringfluoxetinetherapyorearlyaftertreatment

discontinuation(seesection4.4)

Thepossibilityofasuicideattemptisinherentindepressionandmaypersistuntilsignificantremissionoccurs.Itis

generalclinicalexperiencewithalltherapiesfordepressionthattheriskofsuicidemayincreaseintheearlystageof

recovery.

Additionally,insporadiccasesthefollowingreactionshavebeendescribed.Theyneednothowever,haveacasual

connectiontotheuseoffluoxetine:thrombocytopeniaandchangesinthrombocyticfunction;dermal,gastrointestinal

ornasalbleedings;aplasticanaemia,haemolyticanaemia,eosinophilic,pneumonia,malignantneurolepticsymptom

complex,arrhythmia,lossofhair,cytolyticormixedpancreatitis,hyperprolactinemia,vaginalhaemorrhagingafterthe

terminationoffluoxetinetreatment,suicidalthoughts,aggressivebehaviour.

Inrarecasesaprolongationofthebloodcoagulationtimehasbeenobservedand/orhaemorrhaging(suchas

haemotomaintheskin,gynaecologicalhaemorrhaging,haemorrhagingofthegastrointestinalcanalandother

haemorrhagingoftheskinormucousmembranes).

Whenstoppingtreatment,withdrawalsymptomshavebeenreportedinassociationwithSSRIs,althoughtheavailable

evidencedoesnotsuggestthisisduetodependence.Commonsymptomsincludedizziness,paraesthesia,headache,

anxietyandnausea,themajorityofwhicharemildandselflimiting.Fluoxetinehasbeenonlyrarelyassociatedwith

suchsymptoms.Plasmafluoxetineandnorfluoxetineconcentrationsdecreasegraduallyattheconclusionoftherapy,

whichmakesdosagetaperingunnecessaryinmostpatients.

4.9Overdose

Casesofoverdoseoffluoxetinealoneusuallyhaveamildcourse.Symptomsofoverdosehaveincludednausea,

vomiting,seizure,cardiovasculardysfunctionrangingfromasymptomaticarrhythmiastocardiacarrest,pulmonary

dysfunction,andsignsofalteredCNSstatusrangingfromexcitationtocoma.Fatalityattributedtooverdoseof

fluoxetinealonehasbeenextremelyrare.Cardiacandvitalsignsmonitoringarerecommended,alongwithgeneral

symptomaticandsupportivemeasures.Nospecificantidoteisknown.

Forceddiuresis,dialysis,haemoperfusion,andexchangetransfusionareunlikelytobeofbenefit.Activatedcharcoal,

whichmaybeusedwithsorbitol,maybeasmoreeffectivethanemesisorlavage.Inmanagingoverdosage,consider

thepossibilityofmultipledruginvolvement.Anextendedtimeforclosemedicalobservationmaybeneededinpatients

whohavetakenexcessivequantitiesofatricyclicantidepressantiftheyarealsotaking,orhaverecentlytaken,

fluoxetine.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidepressants,selectiveserotoninreuptakeinhibitorsATCcode:N06AB03.

Fluoxetineinhibitstheneuronalre-uptakeofserotonininthecentralnervoussystem,whichisprobablyresponsiblefor

itsaction.

Fluoxetineisnotchemicallyrelatedtotri-,tetracyclicorotherantidepressants.Animalstudieshaveshownthat

fluoxetineisamuchmorepotentinhibitorofserotonin(re-)uptakethanofnoradrenaline(re-)uptake.

Antagonismofmuscarinic,histaminergicand

–adrenergicreceptorsisassociatedwithvariousanticholinergic,

sedativeandcardiovasculareffectsoftricyclicantidepressants.

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5.2Pharmacokineticproperties

Absorption:

Fluoxetineisreadilyabsorbedafteroraladministrationfromthegastrointestinaltractwithapeakplasmaconcentration

ofabout6–8hours.Theabsorptionratedecreasesslightlyundertheeffectoffood,butthetotalquantityoffluoxetine

absorbedisnotaffected;fluoxetinemaythereforebetakenwithorwithoutfood.

Distribution:

Bindingtohumanserumproteins,includingalbuminand

–glycoprotein,isapproximately94.5%invitro.

Fluoxetineisaracemicmixture(50/50)oftheenantiomersR-fluoxetineandS-fluoxetine.

Animalmodelshaveshownthatbothenantiomersarespecificandpotentinhibitorsofserotoninre-uptakewithsimilar

pharmacologicalactivity.

TheS-fluoxetineenantiomeriseliminatedmoreslowlyandisthemainenantiomerinplasmainthesteady-state

situation.

Metabolism:

Fluoxetineisextensivelymetabolisedinthelivertonorfluoxetineandanumberofotherunidentifiedmetabolites.The

onlyidentifiedactivemetabolite,norfluoxetine,isformedbydemethylation.Animalmodelshaveshownthatthe

potencyandselectivityofS-norfluoxetineasaserotoninre-uptakeinhibitorisequivalenttothatofR-andS-

fluoxetine.

R-norfluoxetineisasignificantlylesspotentinhibitorofserotoninre-uptakethantheparentdrug,fluoxetine.The

primaryeliminationisbasedonhepaticmetabolismtoinactivemetaboliteswhichareexcretedviathekidneys.

Elimination:

Therelativelysloweliminationoffluoxetine(half-life4to6days)andoftheactivemetabolitenorfluoxetine(half-life

4to16days)meansthatsteady-stateconcentrationsarereachedafterafewweeksifpatientsreceivecontinuous

administration.Patientstreatedwithdosesof40to80mg/dayforaperiodofupto3yearswerefoundtohave

comparableplasmalevelstopatientstreatedfor4to5weeks.

Plasmaconcentrationsoffluoxetineafterrepeatedadministrationwereshowntobehigherthanexpectedonthebasis

oftheplasmaconcentrationsafterasingleadministration,veryprobablybecausethemetabolismoffluoxetineisnot

proportionatetothedose.Conversely,thepharmacokineticsofnorfluoxetineappeartobelinear.

Age:

Thepharmacokineticsofsingledosesoffluoxetineinhealthyelderlysubjects(over65yearsofage)didnotdiffer

significantlyfromthoseinhealthyyoungersubjects.However,giventhelonghalf-lifeandnon-linearpharmacokinetics

offluoxetine,asingle-dosestudyisnotadequatetoruleoutthepossibilityofalteredpharmacokineticsintheelderly,

particularlyiftheyhaveconcurrentdiseasesorarereceivingmultipledrugs.Theeffectsofageonthemetabolismof

fluoxetinewasstudiedin260depressivebutotherwisehealthypatientsover60yearsofage,treatedfor6weekswith

20mgfluoxetinedaily.Thecombinedfluoxetineandnorfluoxetineplasmaconcentrationsattheendofthe6weeks

were209.3 ±

85.7ng/ml.Nounusual,age-relatedside-effectprofilewasseenintheseelderlypatients.

Hepaticinsufficiency:

Incaseofhepaticinsufficiency,fluoxetineandnorfluoxetinehalf-livesareincreasedto7and12days,respectively.A

lowerorlessfrequentdoseshouldbeconsidered(c.f.4.2Posology).

5.3Preclinicalsafetydata

Thereisnoevidenceofcarcinogenicity,mutagenicityorimpairmentoffertilityfromin-vitrooranimalstudies.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sucrose

Irish Medicines Board

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Date Printed 11/12/2008 CRN 2049123 page number: 9

Peppermintsoluble

Ethanol96%

Benzoicacid(E210)

Hydrochloricacid

Sodiumhydroxide

Purifiedwater

6.2Incompatibilities

Notapplicable

6.3ShelfLife

24months

In-use:1month

6.4Specialprecautionsforstorage

Donotstoreabove25 °

6.5Natureandcontentsofcontainer

Pharmaceuticalgrade,typeIIIamberglassbottleswithpolypropylenechildresistantclosures.Packsize70ml.

Polypropylenedosingcup.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialuse/handling.

7MARKETINGAUTHORISATIONHOLDER

PinewoodLaboratoriesLtd.,tradingasPinewoodHealthcare,

Ballymacarbry,

Clonmel,

Co.Tipperary,

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA281/114/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:13thNovember2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 11/12/2008 CRN 2049123 page number: 10